Indole and pyrazolopyridine compounds as NLRP3 inflammasome inhibitors

Abstract

The present disclosure relates to compounds that act as inhibitors of NLRP3 inflammasomes; pharmaceutical compositions comprising such compounds; and methods of treating conditions associated with inflammation and inflammatory senescence, including sensory neurological diseases and other diseases associated with senescence.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 376,359, filed on September 20, 2022, the contents of which are incorporated herein by reference in their entirety. Background Art

[0003] Aging frailty constitutes a very worrying problem for the overall health and well-being of individuals, and is characterized as a syndrome of multi-system physiological dysregulation. Aging frailty is a geriatric syndrome characterized by weakness, reduced physical activity, decreased motor function, fatigue and unconscious weight loss (Yao, X. et al., Clinics in Geriatric Medicine 27 (1): 79-87 (2011)). In addition, many studies have shown that there is a direct correlation between aging frailty and inflammation (Hubbard, RE et al., Biogerontology 11 (5): 635-641 (2010)). Immunosensing is characterized by a low-grade, chronic systemic inflammatory state, referred to as "inflammatory aging (inflammaging)" (Franceshi, C. et al., Annals of the New York Academy of Sciences 908: 244-254 (2000)). This enhanced inflammatory state or chronic inflammation found in aging and aging frailty can lead to complex reconstruction of immune dysregulation and innate immunity and adaptive immunity.

[0004] Inhibition of the NLRP3 inflammasome, an oligomeric protein complex that includes ASC and caspase-1, mediates inflammation in a large number of preclinical models (Schwaid, AG, J. Med. Chem. 2021, 64(1), 101-122). At the same time, the NLRP3 inflammasome is part of a larger pro-inflammatory pathway, the regulation of which is also being explored. NLRP3 is an inflammasome sensor protein that has been well studied in a variety of disease contexts. Many different indications have been linked to the NLRP3 inflammasome, including aging-related diseases, cryopyrin-associated periodic syndrome (CAPS), nonalcoholic steatohepatitis (NASH), gout, coronary artery disease, Crohn's disease, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, intestinal disorders, acute respiratory distress syndrome (ARDS), amyotrophic lateral sclerosis (ALS), cancer, and skin diseases.

[0005] Inflammation and activation of NLRP3 inflammasomes have also been shown to cause hearing loss (Nakanishi, H. et al., Frontiers in Neurology, 2020, 11, 1-7; Nakanishi, H. et al., PNAS, 2017, E7766-E7775). The inflammation-related hearing loss may be age-dependent (Fischer, N. et al., Gerontology, 2019, 1-7), noise-induced (Le Prell, CG et al. Current Opinion in Physiology, 2020, 18, 32-36), and is the result of viral infection, such as Zika virus and coronavirus (Yee, KT et al., Hearing Research, 2020, 395, 1-15).

[0006] Therefore, the NLRP3 inflammasome is a promising drug target. The broad range of indications in which it is involved suggests that therapeutic agents targeting the NLRP3 inflammasome are needed. Summary of the invention

[0007] Provided herein are compounds that inhibit NLRP3 inflammasomes. Therefore, these compounds can be used to treat a variety of indications, including inflammatory aging and sensory neurological diseases. Also provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another aspect, provided herein is a method of inhibiting NLRP3 inflammasomes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein. DETAILED DESCRIPTION

[0008] Provided herein are compounds that inhibit the NLRP3 inflammasome. Therefore, these compounds and pharmaceutical compositions comprising these compounds can be used to treat a variety of indications, including inflammatory aging and other age-related diseases, such as Alzheimer's disease.

[0009] definition

[0010] Listed below are definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terms as used in this specification and claims unless otherwise limited in specific instances, either individually or as part of a larger group.

[0011] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly used in the art.

[0012] As used herein, the articles "a" and "an" refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element. In addition, the use of the term "include" and other forms (such as "includes", "includes", and "included") is not limiting.

[0013] As used herein, the term "about" will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to a measurable value (such as an amount, duration, etc.), the term "about" is intended to encompass variations of ±20% or ±10% relative to the specified value, including ±5%, ±1%, and ±0.1%, as such variations are suitable for performing the disclosed methods.

[0014] As used herein, the term "administering" and the like refers to providing a therapeutic agent to a subject. There are a variety of techniques for administering therapeutic agents in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0015] The terms "treat," "treated," "treating," or "treatment" include eliminating or alleviating at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment includes alleviating or preventing symptoms of inflammatory aging and age-related disorders.

[0016] As used herein, the term "prevent" or "prevention" means that a condition or disease does not develop (if it has not already developed), or that a condition or disease does not develop further (if it has already developed). Also contemplated is the ability of a treatment to prevent some or all of the symptoms associated with a condition or disease.

[0017] As used herein, the term "patient," "individual," or "subject" refers to a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as sheep, cattle, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is a human.

[0018] As used herein, the terms "effective amount", "pharmaceutically effective amount" and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to provide the desired biological result. The result may be alleviation or relief of the signs, symptoms or causes of a disease, or any other desired change in a biological system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0019] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0020] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic acid or organic acid salts with basic residues such as amines; alkali metal salts or organic salts with acidic residues such as carboxylic acids; etc. The pharmaceutically acceptable salts of the present disclosure include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two; generally, non-aqueous media such as ether, EtOAc, ethanol, isopropanol or acetonitrile are preferred. The phrase "pharmaceutically acceptable salt" is not limited to monosalts or 1:1 salts. For example, "pharmaceutically acceptable salts" also include disalts, such as dihydrochloride. Lists of suitable salts may be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0021] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound that can be used in the present disclosure and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate administration of the compound to a patient or subject. There are a variety of techniques for administering compounds in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0022] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier that is involved in transporting or delivering a compound that can be used in the present disclosure to or to the patient so that it can perform its intended function, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material. Typically, such constructs are transported or delivered from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including that the compound can be used in the present disclosure and is not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered solutions; and other nontoxic compatible substances used in pharmaceutical formulations.

[0023] As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, etc., that are compatible with the activity of the compounds that can be used in the present disclosure and that are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carriers" may also include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that may be included in the pharmaceutical composition are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which reference is incorporated herein by reference.

[0024] As used herein, "inflammaging" is defined as the chronic sterile inflammation associated with many age-related diseases.

[0025] As used herein, "age-related condition" refers to a condition associated with the aging process. Alternatively, the age-related condition is a disease associated with the elderly. Non-limiting examples of age-related diseases include atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension, and Alzheimer's disease. The incidence of all of these diseases increases exponentially with age.

[0026] As used herein, "sensory neurological disease" refers to a condition that affects the brain and nerves found throughout the human body and spinal cord. In some embodiments, the sensory neurological disease is age-related. In certain embodiments, the sensory neurological disease is the result of traumatic brain injury.

[0027] Compound

[0028] Provided herein are compounds that are inhibitors of the NLRP3 inflammasome and are therefore useful in treating inflammatory disorders, including cancer and other proliferative diseases.

[0029] In one aspect, provided herein is a compound selected from the group consisting of compounds in Table 1.

[0030] Table 1

[0031]

[0032]

[0033]

[0034] or a pharmaceutically acceptable salt thereof.

[0035] In another aspect, provided herein is a compound selected from the group consisting of compounds in Table 2.

[0036] Table 2.

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069] or a pharmaceutically acceptable salt thereof.

[0070] In one embodiment, the compound of Table 2 is selected from

[0071]

[0072] or a pharmaceutically acceptable salt thereof.

[0073] In another aspect, provided herein is a compound selected from the group consisting of compounds in Table 3.

[0074] Table 3

[0075]

[0076]

[0077] or a pharmaceutically acceptable salt thereof.

[0078] In one embodiment, the compound is selected from the group consisting of compounds in Table 4.

[0079] Table 4

[0080]

[0081]

[0082]

[0083] or a pharmaceutically acceptable salt thereof.

[0084] In another embodiment, the compound is selected from the group consisting of compounds in Table 5.

[0085] Table 5.

[0086]

[0087] or a pharmaceutically acceptable salt thereof.

[0088] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0089] Compounds disclosed herein may exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, etc.). Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. Chiral centers of known absolute configuration are marked with prefixes R and S, specified by standard sequence rule programs, and, if necessary, preceded by appropriate position markers (Pure & Appl. Chem. 45, 1976, 11-30). Certain examples contain chemical structures displayed or labeled as (R *) or (S *). When (R *) or (S *) is used in the name of a compound or in a chemical diagram of a compound, it is intended to convey that the compound is a pure single isomer at the stereocenter; however, the absolute configuration of the stereocenter has not yet been determined. Thus, a compound designated as (R*) refers to a compound having a pure single isomer with the absolute configuration of (R) or (S) at the stereocenter, and a compound designated as (S*) refers to a compound having a pure single isomer with the absolute configuration of (R) or (S) at the stereocenter.

[0090] It is generally known in the art that any compound that will be converted in vivo to provide a compound disclosed herein is a prodrug within the scope of the present disclosure.

[0091] Compounds provided herein may also include all isotopes of atoms present in intermediates or final compounds. Isotopes include those atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention may be replaced or substituted with isotopes of atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced or substituted with deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange, Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling, James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds are useful in a variety of studies, such as NMR spectroscopy, metabolic experiments and / or assays.

[0092] In embodiments, the compounds provided herein have an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom.

[0093] Treatment

[0094] In one aspect, provided herein is a method of inhibiting the NLRP3 inflammasome in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0095] In another aspect, provided herein is a method of treating inflammation in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0096] In another aspect, provided herein is a method of treating inflammatory senescence in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0097] In another aspect, provided herein is a method of treating cryopyrin-associated periodic syndrome (CAPS) in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0098] In one embodiment, CAPS is selected from the group consisting of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease.

[0099] In another aspect, provided herein is a method of treating a skin disorder in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0100] In one embodiment, the skin disease is selected from the group consisting of psoriasis, urticaria, photoaging of the skin and eczema.

[0101] In another aspect, provided herein is a method of treating a sensory nerve disease in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0102] In one embodiment, the sensory neurological disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), traumatic brain injury, Parkinson's disease and Alzheimer's disease.

[0103] In another aspect, provided herein is a method of treating inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I:

[0104]

[0105] or a pharmaceutically acceptable salt thereof;

[0106] in

[0107] R 1 is C optionally substituted with a substituent selected from the following 1-6 Alkyl: halogen, OH, OC 1-3 Alkyl, NH2, N(H)C 1-3 Alkyl, N(C 1-6 Alkyl)2, C(O)C1-3 Alkyl and C 3-6 Cycloalkyl;

[0108] Each R 2 independently selected from halogen, C 1-3 Haloalkyl, OH, OC 1-3 Alkyl, OC 3-6 Cycloalkyl and C 3-6 Cycloalkyl;

[0109] R 3 Selected from H, halogen, C 1-3 Haloalkyl, OH, OC 1-3 Alkyl, OC 3-6 Cycloalkyl, CN and C 3-6 cycloalkyl; and

[0110] n is 0, 1 or 2.

[0111] In one embodiment,

[0112] R 1 is C optionally substituted with OH 1-6 alkyl;

[0113] Each R 2 independently selected from halo and C 3-6 Cycloalkyl;

[0114] R 3 is a halogen group; and

[0115] n is 1 or 2.

[0116] In another aspect, provided herein is a method for treating inflammatory aging and sensory neurological diseases in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I and at least one pharmaceutically acceptable carrier.

[0117] In one embodiment, the sensory neurological disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), traumatic brain injury, Parkinson's disease and Alzheimer's disease.

[0118] In another aspect, provided herein is a method of inhibiting NLRP3 inflammasome in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I and at least one pharmaceutically acceptable carrier.

[0119] In another embodiment, the compound of formula I is selected from

[0120]

[0121]

[0122]

[0123] or a pharmaceutically acceptable salt thereof.

[0124] In another embodiment, the compound of formula I is selected from

[0125]

[0126] or a pharmaceutically acceptable salt thereof.

[0127] Also provided herein is a method of using the compounds provided herein to treat or improve aging or an aging-related disorder that negatively affects lifespan or quality of life, wherein the aging-related disorder that negatively affects lifespan or quality of life is selected from the group consisting of inflammation, anemia, hyperglycemia, dyslipidemia, hyperinsulinemia, insulin resistance, immunosuppression, liver disease, iron overload, hypertriglyceridemia, impaired skin integrity, wound healing, scarring, pain, allergies, sleep disorders and problems, gastrointestinal disorders and problems, Th1 type inflammation, Th2 type inflammation, inflammatory diseases involving T cell-dependent B cell proliferation, T cell-dependent B cell proliferation, reproduction, allergic reactions, asthma, atherosclerosis, autoimmunity, hypercholesterolemia, chronic inflammation, chronic obstructive pulmonary disease (COPD), Crohn's disease, skin response to tissue injury, fibrosis, hematological oncology, metabolic diseases, cardiovascular disease, organ transplantation, psoriasis, liver fibrosis, dermatitis, pulmonary fibrosis, lung response to respiratory tract infection, restenosis, rheumatoid arthritis, sarcoidosis, tumor stromal biology, systemic lupus erythematosus (SLE), ulcerative colitis, vascular inflammation, and diseases driven or exacerbated by one or more factors selected from the group consisting of alpha smooth muscle actin (αSMA), C D40, CD69, collagen I, collagen III, decorin, e-selectin, eotaxin 3 (CCL26), fibroblast proliferation, human leukocyte antigen-DR isotype (HLA-DR), immunoglobulin G, interferon gamma-induced protein 10 (IP-10 / CXCL10), interferon-inducible T cell alpha chemoattractant (I-TAC / CXCL11), interleukin (IL)-1, IL-1.α., IL-2, IL-6, IL-8 (CXCL8), IL-10, IL-17A, IL-17F, keratin 8 / 81, macrophages The invention relates to a method for treating a subject with a tumor that has a tumor that has a cell colony stimulating factor (M-CSF), matrix metalloproteinase (MMP)-1, MMP-9, monocyte chemoattractant protein 1 (MCP-1), monokine induced by gamma interferon (MIG / CXCL9), plasminogen activator inhibitor 1 (PAI-1), prostaglandin E2 (PGE2), serum amyloid A, T or B cell proliferation, plasminogen activator (tPA), tumor necrosis factor alpha (TNF.α.), vascular cell adhesion molecule (VCAM-1) and vascular endothelial growth factor 2 (VEGFR2), the method comprising: administering a compound provided herein to a subject in need thereof.

[0128] In one aspect, provided herein is a method of reversing the natural aging process in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0129] In another aspect, provided herein is a method of reversing the natural aging process in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0130] In another aspect, provided herein is a method of extending the lifespan of a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0131] In another aspect, provided herein is a method of extending the lifespan of a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0132] In another aspect, provided herein is a method of slowing and alleviating the aging process in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0133] In another aspect, the present invention provides a method of inhibiting or regulating a proinflammatory pathway in a cell, the method comprising contacting the cell with a compound provided herein or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a method of inhibiting or regulating NLRP3 in a cell, the method comprising contacting the cell with a compound provided herein or a pharmaceutically acceptable salt thereof.

[0134] Treatment of cells expressing the NLRP3 inflammasome with the compounds provided herein (in vitro or in vivo) can result in inhibition of proinflammatory pathways and inhibition of downstream events associated with the signaling pathway, such as inflammation or inflammasome senescence.

[0135] In another aspect, provided herein is a method of treating a sensory nerve disease in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0136] In one embodiment, the sensory neurological disease is selected from the group consisting of: hearing loss, hearing impairment, and eye diseases. In one embodiment, the eye disease is retinal and optic nerve damage.

[0137] In another aspect, provided herein is a method of treating an inflammatory disorder in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0138] In one embodiment, the inflammatory disorder is selected from the group consisting of allergic reactions, asthma, atopic dermatitis, atherosclerosis, autoimmune diseases, celiac disease, chronic inflammation, glomerulonephritis, hepatitis, inflammatory bowel disease, reperfusion injury, SARS-CoV-2 infection, transplant rejection, heart disease, diabetes, arthritis, Crohn's disease, ulcerative colitis, non-alcoholic steatohepatitis (NASH), gout, coronary artery disease, rheumatoid arthritis, intestinal disorders, and acute respiratory distress syndrome (ARDS).

[0139] In another embodiment, the inflammatory disorder is a neuroinflammatory disease. In another embodiment, the inflammatory disorder is inner ear inflammation.

[0140] In one embodiment, chronic inflammation comprises tissue inflammation. Tissue inflammation is chronic inflammation limited to a specific tissue or organ. In one embodiment, tissue inflammation comprises, for example, skin inflammation, eye inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreatic inflammation, kidney inflammation, bladder inflammation, stomach inflammation, intestinal inflammation, neuron inflammation, and brain inflammation.

[0141] In another embodiment, chronic inflammation comprises systemic inflammation. Although the processes involved are the same as tissue inflammation, systemic inflammation is not limited to specific tissues, but in fact damages the body, involving the endothelium and other organ systems. When it is attributed to infection, the term sepsis is applicable, particularly for bacterial sepsis the term bacteremia is applicable and particularly for viral sepsis viremia is applicable. Vasodilation and organ dysfunction are serious problems associated with widespread infection, which may lead to septic shock and death.

[0142] In another embodiment, chronic inflammation comprises arthritis. Arthritis includes a group of diseases involving damage to body joints due to synovial inflammation, including but not limited to osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthropathic ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple disease and Behcet disease, septic arthritis, gout (also known as gouty arthritis, crystalline synovitis, metabolic arthritis), pseudogout (calcium pyrophosphate precipitation disease) and Still's disease. Arthritis can affect a single joint (monoarthritis), two to four joints (oligoarthritis) or five or more joints (polyarthritis) and can be an autoimmune disease or a non-autoimmune disease.

[0143] In another aspect, provided herein is a method of treating an age-related disorder in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0144] In one embodiment, the age-related disorder is selected from the group consisting of neurodegeneration, cardiovascular disease, insulin resistance, diabetes, osteoporosis, osteoarthritis, cognitive decline, dementia, frailty, cataracts, arthritis, obesity, hypertension, angina pectoris, congestive heart failure, dyslipidemia, myocardial infarction, vascular disease, respiratory disease, renal disease, cerebrovascular disease, peripheral vascular disease, Alzheimer's disease, diastolic dysfunction, benign prostatic hypertrophy, aortic aneurysm and emphysema.

[0145] In another aspect, provided herein is a method of treating a metabolic disorder in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0146] In one embodiment, the metabolic disorder is selected from the group consisting of diabetes, obesity, cystic fibrosis, and hyperthyroidism.

[0147] In another aspect, provided herein is a method of treating a neurodegenerative disease in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0148] In one embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Batten disease.

[0149] In one aspect, provided herein is a method of treating a disease or disorder of the inner ear in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0150] In one embodiment, the inner ear disease or disorder is selected from the group consisting of hearing loss, hearing impairment, dizziness, Meniere's disease, and tinnitus. In another embodiment, the inner ear disease is hearing loss. In another embodiment, the inner ear disease is hearing impairment.

[0151] In another embodiment, the hearing loss is age-related, noise-induced, or the result of a viral infection. In another embodiment, the viral infection is Zika virus or coronavirus.

[0152] IC 50 The value determines the potency of the inhibitor.50 A compound with a lower IC value, as determined under substantially similar conditions 50 The compounds with higher values ​​are more effective inhibitors.

[0153] In one embodiment of the method, the subject is a human.

[0154] In another aspect, the present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating or preventing a disease in which the NLRP3 inflammasome plays a role.

[0155] In one aspect, provided herein is a method of treating a disorder selected from the group consisting of: autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immune-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease. In other embodiments, the disorder is selected from proliferative disorders and neurodegenerative disorders.

[0156] One aspect of the present disclosure provides compounds that can be used to treat diseases, disorders and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases and neurodegenerative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer.

[0157] Thus, in one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0158] In one embodiment, the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, stomach cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, colorectal cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, myeloid disorders, lymphoid disorders, Hodgkin's disease, hairy cell cancer, buccal cavity and pharyngeal (oral) cancer, lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colon cancer, rectal cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer, chronic myeloid leukemia (CML) and leukemia.

[0159] In another embodiment, the cancer is selected from the group consisting of myeloma, lymphoma, or a cancer selected from gastric cancer, renal cancer, head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin's lymphoma, and lung cancer.

[0160] In one embodiment, the cancer is selected from the group consisting of prostate cancer, colon cancer, lung cancer, head and neck squamous cell carcinoma, esophageal cancer, hepatocellular carcinoma, melanoma, sarcoma, gastric cancer, pancreatic cancer, ovarian cancer, breast cancer.

[0161] In one embodiment, the cancer is selected from the group consisting of a tumor, a neoplasm, a carcinoma, a sarcoma, a leukemia, a lymphoma, etc. By way of example, cancer includes, but is not limited to, mesothelioma, leukemia, and lymphoma, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotropic virus (HTLV), such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Other examples include myelodysplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors and soft tissue sarcomas, common adult solid tumors such as head and neck cancer (e.g., oral cancer, laryngeal cancer, nasopharyngeal cancer and esophageal cancer), genitourinary cancer (e.g., prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, testicular cancer), lung cancer (e.g., small cell cancer and non-small cell cancer), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors associated with Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Other exemplary cancer forms that can be treated with the compounds of the invention include, but are not limited to, bone or smooth muscle cancer, stomach cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0162] Other cancers that the compounds described herein can be used to treat are, for example, colon cancer, familial adenomatous polyposis carcinomas and hereditary non-polyposis colorectal cancer or melanoma. In addition, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (marrow and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, testicular cancer, urethral cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, gallbladder cancer, bronchial cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmacytoma.

[0163] In another aspect, provided herein is the use of one or more compounds disclosed herein in the manufacture of a medicament for treating cancer, including but not limited to the various types of cancer disclosed herein.

[0164] In some embodiments, the compounds of the present disclosure can be used to treat cancers such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer; and myeloproliferative disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, the compounds of the present disclosure can be used to treat hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, and acute lymphocytic leukemia (ALL).

[0165] Administration / dosage / formulation

[0166] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and aromatics.

[0167] Injectable preparations (e.g., sterile injectable aqueous or oily suspensions) can be prepared using suitable dispersing or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, for example in the form of 1,3-butanediol solutions. Among acceptable vehicles and solvents, water, Ringer's solution USP and isotonic sodium chloride solution can be used. In addition, sterile, fixed oils are routinely used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectables.

[0168] In order to prolong the effect of the drug, it is often necessary to slow down the absorption of the drug injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the drug depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a drug form administered parenterally can be achieved by dissolving or suspending the drug in an oil vehicle.

[0169] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity and releases the active compound.

[0170] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0171] The active compound may also be in a microencapsulated form using one or more excipients as mentioned above. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings, controlled release coatings and other coatings known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (such as sucrose, lactose or starch). According to conventional practice, such dosage forms may also include other substances, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, in addition to inert diluents. In the case of capsules, tablets and pills, the dosage form may also include a buffer.

[0172] Dosage forms for topical or transdermal administration of the disclosed compounds include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Where necessary, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers. Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also encompassed within the scope of the present disclosure.

[0173] Ointments, pastes, creams and gels may contain, in addition to the active compounds of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0174] Powders and sprays may contain, in addition to a compound of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons.

[0175] Transdermal patches have the additional advantage of providing controlled delivery of compounds into the body. Such dosage forms can be prepared by dissolving or dispensing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0176] The compounds of the present disclosure may be administered intratympanically, where an elongated needle is passed through the ear canal and through the ear drum, administering the drug to the middle ear space where it is absorbed by the inner ear.

[0177] According to the treatment methods disclosed herein, a subject (such as a human or other animal) is treated or prevented from a condition by administering a therapeutically effective amount of a compound of the present disclosure to the subject in an amount and for a desired time to achieve the desired result. As used herein, the term "therapeutically effective amount" of a compound of the present disclosure means an amount of the compound sufficient to alleviate the symptoms of the subject's condition. As is well known in the medical field, the therapeutically effective amount of a compound of the present disclosure should be at a reasonable benefit / risk ratio applicable to any medical treatment.

[0178] In general, the compounds of the present disclosure will be administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, via any of the usual and acceptable modes known in the art. The therapeutically effective amount can vary widely according to the severity of the disease, the age and relative health of the subject, the efficacy of the compound used, and other factors. In general, when the daily dose is about 0.03 to 2.5 mg per kilogram of body weight, satisfactory results can be obtained systemically. In larger mammals (e.g., humans), the indicated daily dose is in the range of about 0.5 mg to 100 mg, preferably, for example, administered up to four times a day in divided doses or administered in a sustained release form. Unit dosage forms suitable for oral administration include about 1 to 50 mg of active ingredient.

[0179] In certain embodiments, the therapeutic amount or dosage of the compounds of the present disclosure may be in the range of about 0.1 mg / Kg to about 500 mg / Kg or about 1 to about 50 mg / Kg. In general, the treatment regimen according to the present disclosure includes administering about 10 mg to about 1000 mg of one or more compounds of the present disclosure to patients in need of such treatment in a single or multiple doses per day. The therapeutic amount or dosage will also vary depending on the route of administration and the possibility of using other agents together.

[0180] After the subject's condition is improved, a maintenance dose of the compounds, compositions or combinations of the present disclosure may be administered, if necessary. Subsequently, the dose or frequency of administration, or both, may be reduced to a level that maintains the improved condition as the symptoms dictate; treatment should be stopped when the symptoms have been alleviated to the desired level. However, after any recurrence of disease symptoms, the subject may require long-term intermittent treatment.

[0181] However, it should be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular patient will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the time of administration, route of administration and excretion rate of the specific compound used; the duration of treatment; the drugs used in combination or in conjunction with the specific compound used; and similar factors well known in the medical field.

[0182] The present disclosure also provides a pharmaceutical combination, such as a kit, comprising a) a first agent, the first agent being a compound of the present disclosure as disclosed herein, in free form or in the form of a pharmaceutically acceptable salt, and b) at least one co-agent. The kit may include instructions for its administration.

[0183] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphate esters, glycine, sorbic acid or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylene polyoxypropylene block polymers; lanolin; sugars such as lactose, glucose and sucrose. Sugar; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffered solutions. In addition, nontoxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) and colorants, anti-adherents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants may also be present in the composition at the discretion of the formulator. The protein kinase inhibitor or its pharmaceutically acceptable salt can be formulated into a pharmaceutical composition for administration to animals or humans. These pharmaceutical compositions comprising an amount of a protein inhibitor effective to treat or prevent a protein kinase-mediated disorder and a pharmaceutically acceptable carrier are other embodiments of the present disclosure.

[0184] Pill Box

[0185] In one aspect, provided herein is a kit comprising a compound capable of inhibiting NLRP3 inflammasome activity selected from one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and instructions for treating a disorder associated with NLRP3 inflammasome.

[0186] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting NLRP3 inflammasome activity selected from the compounds disclosed herein or a pharmaceutically acceptable salt thereof.

[0187] In another aspect, provided herein is a kit comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof for treating any of the indications disclosed herein.

[0188] Those skilled in the art will recognize or be able to determine many equivalents of the specific procedures, embodiments, claims and embodiments described herein using only routine experiments. Such equivalents are considered to be within the scope of the present disclosure and are covered by the claims appended hereto. For example, it should be understood that modifications to reaction conditions using alternatives recognized in the art and using only routine experiments are within the scope of the present application, including but not limited to reaction time, reaction scale / volume and experimental reagents (such as solvents, catalysts), pressure, atmospheric conditions (e.g., nitrogen atmosphere) and reducing / oxidizing agents.

[0189] It should be understood that, in the case where values ​​and ranges are provided anywhere herein, all values ​​and ranges encompassed by these values ​​and ranges are intended to be encompassed within the scope of the present disclosure. In addition, all values ​​within these ranges and the upper or lower limits of the range of values ​​are also encompassed by the present application.

[0190] The following examples further illustrate various aspects of the present disclosure. However, they are in no way intended to limit the teachings of the present disclosure as set forth.

[0191] Example

[0192] The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. Unless otherwise indicated, the practice of the present disclosure will employ conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art.

[0193] Example 1: Synthesis Procedure

[0194] Solution 1.

[0195]

[0196] TBAF (1M, 4.03mL, 1.1 equivalents), TEA (740.98mg, 7.32mmol, 1.02mL, 2 equivalents), CuI (139.46mg, 732.27umol, 0.2 equivalents) and Pd (PPh3) 2Cl2 (256.99mg, 366.14umol, 0.1 equivalents) were added to a glass bottle (40mL) containing a solution of compound 1 (1g, 3.66mmol, 1 equivalent) and 2 compound 2 (506.30mg, 3.66mmol, 1 equivalent) in DMF (10mL). The mixture was stirred at 100°C under N2 atmosphere for 12 hours. The reaction mixture was poured into water (60mL) and extracted with EtOAc (50mL x 5). The combined organic layer was dried over [Na2SO4], filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 5 / 1), and the purified solution was concentrated in vacuo to give compound 3 (280 mg, 1.08 mmol, 29.61% yield) as a brown oil. LCMS: Rt=0.530 min, m / z=259.1 (M+H) +

[0197] To a round-bottom flask (50 mL) containing a solution of compound 3 (280 mg, 1.08 mmol, 1 eq.) in EtOH (3 mL) and H2O (1 mL) was added LiOH·H2O (136.46 mg, 3.25 mmol, 3 eq.). The mixture was stirred at 20 °C for 1 hour. The organic solvent was evaporated under vacuum, the resulting mixture was acidified to pH 4 with 1N HCl, filtered, the filter cake was washed with water (20 mL), then dissolved in EtOH (20 mL), and concentrated in vacuo to give compound 4 (240 mg, 1.04 mmol, 96.16% yield) as a yellow solid, which was used in the next step. LCMS: Rt=0.307 min, m / z=229.1 (MH) +

[0198] EDCI (164.09 mg, 855.95 umol, 1 eq.) and DMAP (6.97 mg, 57.06 umol, 0.1 eq.) were added to a round-bottom flask (50 mL) containing a solution of compound 4 (131.39 mg, 570.63 umol, 1 eq.) and compound 5 (200 mg, 570.63 umol, 1 eq.) in DCM (10 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=5 / 1 to 0 / 1), and the purified solution was concentrated in vacuo to give compound 6 (285 mg, 506.46 umol, 88.75% yield) as a yellow oil. LCMS: Rt=0.549 min, m / z=563.3 (M+H) +

[0199] LiBH4 (33.10 mg, 1.52 mmol, 3 equiv.) was added to a solution of compound 6 (285 mg, 506.46 umol, 1 equiv.) in MeOH (5 mL) at 0 ° C. The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was poured into a saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (30 mL x 3), and the combined organic phases were dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, EtOAc: methanol = 1 / 0 to 10 / 1), and the purified solution was concentrated in vacuo to give compound 7 (150 mg, 280.52 umol, 55.39% yield) as a yellow oil. LCMS: Rt = 0.452 min, m / z = 535.3 (M+H) +

[0200] BAST (124.13 mg, 561.04 umol, 122.90 uL, 2 equiv.) was added to a glass bottle (40 mL) containing a solution of compound 7 (150 mg, 280.52 umol, 1 equiv.) in DCM (10 mL) at 0 ° C. The mixture was stirred at 20 ° C for 10 min. The reaction mixture was cooled in an ice bath, then poured into a saturated NaHCO3 aqueous solution (20 mL) and extracted with DCM (30 mL x 3), the combined organic phases were dried and concentrated under vacuum to give a residue. The residue was purified by preparative-TLC (SiO2, PE: EtOAc = 0: 1), and the purified solution was concentrated in vacuo to give compound 8 (40 mg, 74.53 umol, 26.57% yield) as a colorless oil. LCMS: Rt = 0.530 min, m / z = 537.3 (M + H) +

[0201] CsF (99.06 mg, 652.12 umol, 24.04 uL, 10 equiv) was added to a glass bottle (8 mL) containing a solution of compound 8 (35 mg, 65.21 umol, 1 equiv) in DMF (1 mL). The mixture was stirred at 100 ° C for 12 hours. The mixture was stirred at 100 ° C for 60 hours. The mixture was stirred at 120 ° C for 24 hours. The reaction mixture was filtered. The filtrate was purified by preparative-HPLC (column: Water xbridge 150*25mm 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 34%-64%, 8min). The purified solution was lyophilized to give 001 (5.9 mg, 14.52 umol, 22.26% yield, 100% purity) as a white solid. LCMS: Rt=0.379min, m / z=407.0(M+H) + 1H NMR (400MHz, chloroform-d)δ=12.28-12.15(m,1H),8.45-8.39(m,1H),8.26-8.21(m,1H),7.39-7.34(m,1H),6 .95-6.90(m,2H),5.93-5.69(m,2H),4.95-4.86(m,2H),4.15-4.04(m,2H),3.01-2.92(m,3H),1.49(br s,1H),1.49-1.44(m,3H),0.93-0.87(m,2H),0.87(br s,2H).

[0202] Compound 012 was prepared in a manner similar to Scheme 1 using TFA instead of CsF and obtained as an off-white solid (57 mg, 123.90 umol, 72.57% yield, and 99% purity). LCMS: Rt=0.423 min, m / z=456.4 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.09-11.81 (m, 1H), 8.44 (d, J = 2.6 Hz, 1H), 8.29 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.45-7.40 (m, 1H), 7.38-7.33 (m, 2H), 7.16-7.09 (m, 1H), 5.93-5.77 (m, 2H), 5.01 (s, 2H), 4.44-4.35 (m, 2H), 3.05 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0203] Compound 013 was prepared in a similar manner to Scheme 1 using DAST instead of BAST and obtained as a white solid (2.3 mg, 5.83 umol, 11.77% yield, 100% purity). LCMS: Rt=0.351min, m / z=395.2(M+H+).1HNMR: (chloroform-d): δ12.20(1H,br s),8.41(1H,d,J=2.5Hz),8.24(1H,s),7.39(1H,d,J=8.3Hz),6.88-6.98(2H,m),5.69-5.91(2H,m),4.91( 2H, s), 4.10 (2H, q, J = 7.0Hz), 2.97 (3H, s), 2.49 (2H, q, J = 7.5Hz), 1.47 (3H, t, J = 7.0Hz), 1.23-1.28 (3H, m).

[0204] Compound 014 was prepared in a manner similar to Scheme 1 and obtained as a white solid (6.8 mg, 17.83 umol, 22.67% yield, 99.2% purity). LCMS: Rt=0.472 min, m / z=379.0 (M+H) + 1H NMR (400MHz, chloroform-d) δ = 12.29-12.14 (m, 1H), 8.28-8.18 (m, 2H), 7.39 (d, J = 7.9Hz, 1H), 6.99-6.87 (m, 2H), 5.1 5-5.07(m,2H),4.95-4.86(m,2H),4.11(q,J=6.9Hz,2H),3.01-2.94(m,3H),2.12(s,3H),1.50-1.44(m,3H).

[0205] Compound 018 was prepared in a manner similar to Scheme 1 and obtained as a white solid (10.01 mg, 20.37 umol, 35.18% yield, and 100% purity). LCMS: Rt = 0.385 min, m / z = 492.1 (M + H +). H NMR: (400 MHz, chloroform-d) δ = 8.51 (br s, 1H), 8.33 (s, 1H), 7.47 (s, 1H), 7.41-7.28 (m, 3H), 6.92 (d, J = 9.3 Hz, 1H), 6.03-5.86 (m, 2H), 4.98 (s, 2H), 3.86-3.72 (m, 1H), 3.09 (s, 3H), 0.84 (br d, J = 5.9 Hz, 2H), 0.72 (br s, 2H).

[0206] Compound 019 was prepared in a manner similar to Scheme 1 and obtained as a white solid (6.5 mg, 13.66 umol, 14.99% yield, 99.5% purity). LCMS: Rt = 0.390 min, m / z = 474.0 (M+H) + 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.13-12.39 (m, 1H) 8.46-8.52 (m, 1H) 8.27-8.35 (m, 1H) 7.64-7.68 (m, 2H) 7.57-7.61 (m, 1H) 7.50-7.55 (m, 1H) 7.25-7.26 (m, 1H) 6.90-6.93 (m, 1H) 5.83-6.02 (m, 2H) 4.95-5.01 (m, 2H) 3.72-3.81 (m, 1H) 3.06-3.12 (m, 3H) 0.79-0.84 (m, 2H) 0.68-0.74 (m, 2H).

[0207] Compound 020 was prepared in a manner similar to Scheme 1 and obtained as a white solid (7 mg, 14.45 umol, 12.69% yield). 1 H-NMR: (400MHz, chloroform-d) δ = 12.64-11.79 (m, 1H), 8.44 (d, J = 2.3Hz, 1H), 8.28 (s, 1H), 7.23 (s, 1H), 6.91-6.81 (m, 4H), 5.91-5.77 (m, 2H) ),4.96(s,2H),3.76(tt,J=2.9,5.8Hz,1H),3.07(s,3H),0.83-0.79(m,2H),0.75-0.70(m,2H).LCMS: Rt=0.419min, m / z=484.9(M+H + ).

[0208] Compound 022 was prepared in a manner similar to Scheme 1 and obtained as a white solid (6.5 mg, 13.41 umol, 32.88% yield, 99.6% purity). LCMS: Rt=0.435 min, m / z=483.2 (M+H) +1H NMR (400 MHz, chloroform-d) δ = 12.62-11.60 (m, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.31-8.25 (m, 1H), 7.36-7.32 (m, 3H), 7.25-7.20 (m, 2H), 6.91-6.86 (m, 1H), 5.94-5.76 (m, 2H), 4.99-4.92 (m, 2H), 3.80-3.71 (m, 1H), 3.10-3.04 (m, 3H), 0.83-0.76 (m, 2H), 0.75-0.68 (m, 2H).

[0209] Compound 027 was prepared in a manner similar to Scheme 1 and obtained as a white solid (15.5 mg, 32.76 umol, 48.88% yield, 98.6% purity). LCMS: Rt=0.424 min, m / z=467.1 (M+H) + 1H NMR (400MHz, chloroform-d) δ = 8.45 (d, J = 2.5Hz, 1H), 8.28 (s, 1H), 7.43-7.32 (m, 1H), 7.24 (s, 1H), 7.12 (br d,J=7.4Hz,1H),7.09-7.04(m,2H),6.89(d,J=8.9Hz,1H),5.95-5.79(m,2H),4.96(s,2H),3.76(br d,J=3.0Hz,1H),3.08(s,3H),0.91-0.86(m,2H),0.80(br d,J=5.5Hz,2H).

[0210] Compound 046 was prepared in a manner similar to Scheme 1 and obtained as a white solid (45 mg, 92.32 umol, 38.02% yield, 100% purity). LCMS: Rt=0.445 min, m / z=488.1 (M+H) + 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.11-12.36 (m, 1H) 8.40-8.45 (m, 1H) 8.26-8.31 (m, 1H) 7.87-7.92 (m, 1H) 7.74-7.80 (m, 2H) 7.62-7.67 (m, 1H) 7.54-7.59 (m, 1H) 7.51 (d, J = 7.63 Hz, 1H) 5.75-5.92 (m, 2H) 4.93-5.01 (m, 2H) 4.42 (q, J = 7.13 Hz, 2H) 3.22 (s, 3H) 1.33-1.41 (m, 3H).

[0211] Compound 071 was prepared in a manner similar to Scheme 1 using TFA instead of CsF and obtained as a white solid (5.4 mg, 11.08 umol, 22.65% yield, 99.1% purity). LCMS: Rt=0.432 min, m / z=483.2 (M+H) + 1H NMR (400 MHz, CHLOROFORM-d) δ=1 8.44 (d, J=2.8 Hz, 1H), 8.28 (s, 1H), 7.38-7.31 (m, 3H), 7.23 (s, 2H), 6.89 (d, J=9.0 Hz, 1H), 5.93-5.76 (m, 2H), 4.96 (s, 2H), 3.75 (td, J=3.0, 5.8 Hz, 1H), 3.07 (s, 3H), 0.84-0.77 (m, 2H), 0.75-0.69 (m, 2H).

[0212] Compound 082 was prepared in a manner similar to Scheme 1 using TFA instead of CsF and obtained as a white solid (10.38 mg, 21.98 umol, 43.80% yield, 99% purity). LCMS: Rt=0.370 min, m / z=478.1 (M+Na + ) 1 HNMR: (400MHz, chloroform-d)δ=12.35(br d,J=5.4Hz,1H),8.48-8.19(m,2H),7.77(s,1H),7.69(d,J=7.9Hz,1H),7.63(d,J =7.8Hz,1H),7.55-7.48(m,1H),7.41(d,J=1.0Hz,1H),7.32(d,J=7.8Hz,1H),7.0 9(dd,J=1.3,7.7Hz,1H),5.18(s,2H),5.01(s,2H),3.77(td,J=2.9,5.9Hz,1H),3 .34(q,J=7.0Hz,2H),1.32(t,J=7.1Hz,3H),0.85-0.79(m,2H),0.78-0.72(m,2H).

[0213] Compound 092 was prepared in a manner similar to Scheme 1 using TFA instead of CsF and obtained as a white solid (20.4 mg, 41.22 umol, 36.81% yield, 100% purity). LCMS: Rt=0.416 min, m / z=495.1 (M+H +)1HNMR (400MHz, chloroform-d)δ=12.97-11.80(m,1H),8.37-8.28(m,2H),7.38-7.32(m,3H),7.23(br s,1H),7.17(s,1H),6.84(br d,J=8.9Hz,1H),5.25-5.15(m,2H),4.99(s,2H),3.73(br d,J=2.6Hz,1H),3.35(q,J=6.6Hz,2H),1.33(br t,J=6.8Hz,3H),0.82-0.76(m,2H),0.72(br s,2H).

[0214] Compound 093 was prepared in a manner similar to Scheme 1 and obtained as a white solid (4.2 mg, 8.98 umol, 26.43% yield, 98% purity). LCMS: Rt=0.383 min, m / z=459.0 (M+H) + 1H NMR (400 MHz, CHLOROFORM-d) δ=12.48-11.84 (m, 1H), 8.26 (br d, J=4.6 Hz, 2H), 7.49-7.38 (m, 1H), 6.91-6.77 (m, 3H), 5.13 (s, 2H), 4.98-4.82 (m, 2H), 4.19 (q, J=7.0 Hz, 2H), 3.03 (s, 3H), 1.54 (t, J=7.0 Hz, 3H).

[0215] Compound 105 was prepared in a manner similar to Scheme 1 and obtained as a white solid (5.8 mg, 12.16 umol, 23.71% yield, and 95.3% purity). LCMS: Rt = 0.384 min, m / z = 454.13 (M+H + ) 1 H NMR: (400MHz, chloroform-d) δ = 12.37-12.07 (m, 1H), 8.45 (d, J = 2.5Hz, 1H), 8.27 (s, 1H), 7.59 (br s,1H),7.45(d,J=4.9Hz,1H),7.27-7.25(m,1H),7.19-7.08(m,1H),6.98-6.86(m,1H ),5.94-5.78(m,2H),4.95(s,2H),3.91-3.83(m,1H),3.07(s,3H),0.91-0.85(m,4H).

[0216] Compound 110 was prepared in a manner similar to Scheme 1 and obtained as a white solid (3.7 mg, 8.06 umol, 15.71% yield, 99% purity). LCMS: Rt = 0.372 min, m / z = 455.1 (M+H + ).HNMR: (400MHz, CHLOROFORM-d)δ=12.53-12.11(m,1H),8.48(s,1H),8.29(s,1H),7.56(d,J=1.3Hz,1H),7.37-7.31(m,2H),7.25(s,1H),6.90(d,J=10.0Hz,1H),6.07-5.80(m,2H),4.96(s,2H),3.80(d,J=3.4Hz,1H),3.08(s,3H),0.83(t,J=5.0Hz,2H),0.81-0.77(m,2H).

[0217] Compound 173 was prepared in a manner similar to Scheme 1 using TFA instead of CsF and obtained as a white solid (14.2 mg, 31.05 umol, 36.06% yield, 98.5% purity). LCMS: Rt=0.373 min, m / z=451.3 (M+H + ) 1 HNMR (400MHz, chloroform-d) δ = 12.24 (br s,1H),8.35(d,J=2.1Hz,1H),7.40-7.28(m,4H),7.09-7.00(m,3H),5.86(s,1H),5.89-5.70(m,1H) ,5.74(s,1H),5.11(s,2H),4.07(q,J=7.0Hz,2H),3.04(s,3H),2.81(s,3H),1.38(t,J=6.9Hz,3H).

[0218] Compound 183 was prepared in a manner similar to Scheme 1 using TFA instead of CsF and obtained as a white solid (29.0 mg, 60.80 umol, 25.33% yield, 99.5% purity). LCMS: Rt=0.393 min, m / z=477.0 (M+H + ) 1 HNMR: 1H NMR (400MHz, chloroform-d) δ = 12.64-12.08 (m, 1H), 8.30 (br d,J=13.6Hz,2H),7.45(s,1H),7.38(s,1H),7.36-7.30(m,4H),7.08-7.04(m,1H),5.17(s,2H),5.03- 4.98(m,2H),3.75(tt,J=3.0,5.8Hz,1H),3.38-3.31(m,2H),1.32(t,J=7.1Hz,3H),0.84-0.73(m,4H).

[0219] Solution 2

[0220]

[0221] EDCI (220.97 mg, 1.15 mmol, 1.5 equiv) and DMAP (9.39 mg, 76.85 umol, 0.1 equiv) were added to a solution of compound 1 (200 mg, 768.46 umol, 1 equiv) and compound 2 (323.20 mg, 922.16 umol, 1.2 equiv) in DCM (4 mL). The mixture was stirred at 20 ° C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, PE: EtOAc = 0: 1). Compound 3 (450 mg, 607.36 umol, 79.04% yield, 80% purity) was obtained as a yellow oil. LCMS: Rt = 0.525 min, m / z = 593.9 (M + H + )

[0222] To a solution of compound 3 (150 mg, 253.07 umol, 1 equiv.) in DCM (2 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 106.74 equiv.). The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (column: Phenomenex luna C18150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 40%-70%, 10 min). Then, the purified solution was lyophilized to give the product. 002 (24.6 mg, 52.98 umol, 20.94% yield, 99.6% purity) was obtained as a white solid. LCMS: Rt=0.455 min, m / z=462.17 (M+H + ) 1H NMR: (400MHz, DMSO-d6) δ = 14.10-13.56 (m, 1H), 8.60 (br s, 1H), 8.44 (br s, 1H), 7.43 (br d,J=6.3Hz,2H),7.40-7.30(m,2H),7.25-7.08(m,3H),5.07(br s,2H),4.13(br s,2H),3.99(s,3H),3.07(br s,3H),1.37-1.19(m,3H).

[0223] Compound 021 was prepared in a manner similar to Scheme 2 using CsF instead of TFA and obtained as a green solid (10.2 mg, 21.75 umol, 26.07% yield, 100% purity). LCMS: Rt=0.361 min, m / z=469.0 (M+H) + 1HNMR (400MHz, chloroform-d) δppm 12.20-12.70(m,1H)8.26-8.38(m,2H)7.60-7.64(m,1H)7.43-7.46(m,1H)7.29(d,J=4.00Hz,1H)7.09(dd,J=8.07, 1.06Hz,1H)6.89-6.93(m,1H)5.17-5.23(m,2H)4.97(s,2H)3.86-3.95(m,1H)3.05-3.09(m,3H)0.88-0.93(m,4H).

[0224] Compound 028 was prepared in a manner similar to Scheme 2 and obtained as a white solid (17.3 mg, 37.15 umol, 36.72% yield, 99.4% purity). LCMS: Rt=0.401 min, m / z=463.4 (M+H) + 1H NMR (400 MHz, chloroform-d) δ = 8.42-8.32 (m, 2H), 7.46-7.43 (m, 2H), 7.37-7.29 (m, 4H), 7.11 (d, J = 7.8 Hz, 1H), 5.23 (s, 2H), 4.98 (s, 2H), 3.80-3.75 (m, 1H), 3.09 (s, 3H), 0.85-0.79 (m, 2H), 0.78-0.72 (m, 2H).

[0225] Compound 032 was prepared in a manner similar to Scheme 2 and obtained as a white solid (3.5 mg, 7.31 umol, 7.42% yield, 100% purity). LCMS: Rt=0.408 min, m / z=478.16 (M+H + ) 1H NMR: 1 H NMR (400MHz, chloroform-d)δ=12.46-12.28(m,1H),8.34-8.34(m,1H),8.40-8.33(m,1H),8.27(s,1H),7.36-7.33(m,3H),7.23(br d,J=4.0Hz,1H),7.18(s,1H),6.85(d,J=8.9Hz,1H),4.97(s,2H),3.77-3.71(m,1 H), 3.34 (q, J = 7.0Hz, 2H), 3.02 (s, 3H), 1.33 (t, J = 7.1Hz, 3H), 0.81-0.71 (m, 4H).

[0226] Compound 033 was prepared in a manner similar to Scheme 2 and obtained as a white solid (10.2 mg, 23.46 umol, 43.85% yield, and 99% purity). LCMS: Rt = 0.452 min, m / z = 450.9 (M+H + ).1HNMR:1H NMR(chloroform-d):δ12.05-12.27(1H,m),9.05(1H,s),8.22(1H,s),7.33-7.44(5H,m),7.23(1H,s),6.86-6.91(1H,m),5.12(2H,s),3.67-3.81(1H,m),3.08(3H,s),2.87(3H,s),0.75-0.81(2H,m),0.68-0.74(2H,m).

[0227] Compound 038 was prepared in a manner similar to Scheme 2 and obtained as a white solid (53.1 mg, 118.40 umol, 42.83% yield, 100% purity). LCMS: Rt=0.388 min, m / z=449.4 (M+H) + 1H NMR (400 MHz, chloroform-d) δ = 8.57 (s, 1H), 8.50 (s, 1H), 7.42-7.34 (m, 1H), 7.24 (s, 1H), 7.15-7.04 (m, 3H), 6.93-6.88 (m, 1H), 4.98 (s, 2H), 3.80-3.72 (m, 1H), 3.13 (s, 6H), 0.85-0.78 (m, 2H), 0.76-0.70 (m, 2H).

[0228] Compound 048 was prepared in a manner similar to Scheme 2 and obtained as a white solid (15.4 mg, 32.86 umol, 27.94% yield, 99.2% purity). LCMS: Rt=0.391 min, m / z=465.3 (M+H) + 1H NMR (400 MHz, chloroform-d) δ = 12.27-11.83 (m, 1H), 8.31-8.13 (m, 2H), 7.38-7.32 (m, 3H), 7.23 (s, 2H), 6.88 (dd, J = 1.1, 9.0 Hz, 1H), 4.92 (s, 2H), 3.75 (tt, J = 2.9, 5.9 Hz, 1H), 3.10-3.03 (m, 3H), 2.92-2.85 (m, 3H), 0.83-0.76 (m, 2H), 0.76-0.68 (m, 2H).

[0229] Compound 055 was prepared in a manner similar to Scheme 2 and obtained as a white solid (3.8 mg, 8.18 umol, 23.76% yield, and 97% purity). LCMS: Rt = 0.452 min, m / z = 450.9 (M + H +). 1H NMR: (chloroform-d): δ 12.22 (1H, br s), 8.33-8.43 (2H, m), 7.28-7.41 (4H, m), 7.00-7.11 (3H, m), 6.49 (1H, q, J = 7.0 Hz), 5.71-5.93 (2H, m), 3.99-4.15 (2H, m), 2.81 (3H, s), 1.88 (3H, d, J = 7.3 Hz), 1.37 (3H, t, J = 7.0 Hz).

[0230] Compound 062 was prepared in a manner similar to Scheme 2 and obtained as a colorless oil (11.5 mg, 25.54 umol, 38.90% yield, 99.6% purity). LCMS: Rt=0.382 min, m / z=449.1 (M+H + ).

[0231] Compound 064 was prepared in a manner similar to Scheme 2 and obtained as a white solid (53.6 mg, 123.14 umol, 57.54% yield, 98.9% purity). LCMS: Rt=0.372 min, m / z=431.2 (M+H+) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.69-0.75 (m, 2H) 0.76-0.82 (m, 2H) 3.09-3.18 (m, 6H) 3.70-3.80 (m, 1H) 4.96-5.02 (m, 2H) 6.91 (dd, J=9.01, 1.38 Hz, 1H) 7.24 (s, 1H) 7.32-7.36 (m, 2H) 7.36-7.39 (m, 1H) 7.39-7.45 (m, 2H) 8.51 (s, 1H) 8.62 (s, 1H).

[0232] Compound 065 was prepared in a manner similar to Scheme 2 and obtained as a white solid (16.7 mg, 35.23 umol, 22.93% yield, 96.1% purity). LCMS: Rt = 0.356 min, m / z = 456.4 (M+H+) 1 H NMR (400 MHz, CHLOROFORM-d) δ = 12.66-12.38 (m, 1H), 8.50-8.45 (m, 1H), 8.42 (s, 1H), 7.68-7.64 (m, 2H), 7.61-7.57 (m, 1H), 7.56-7.51 (m, 1H), 7.25 (s, 1H), 6.91 (s, 1H), 5.01-4.89 (m, 2H), 3.80-3.73 (m, 1H), 3.13-3.08 (m, 3H), 3.07-3.02 (m, 3H), 0.85-0.78 (m, 2H), 0.75-0.68 (m, 2H).

[0233] Compound 068 was prepared in a manner similar to Scheme 2 and obtained as a yellow oil (13.6 mg, 28.14 umol, 23.93% yield, 96.2% purity). LCMS: Rt = 0.407 min, m / z = 465.3 (M+H+). 1 H NMR: (400 MHz, chloroform-d) δ = 13.01-12.56 (m, 1H), 9.41 (s, 1H), 8.46 (s, 1H), 7.35 (t, J = 4.3 Hz, 3H), 7.23 (s, 2H), 6.90 (d, J = 9.0 Hz, 1H), 5.14 (s, 2H), 3.75 (tt, J = 2.9, 5.8 Hz, 1H), 3.12 (s, 3H), 3.01 (s, 3H), 1.25 (t, J = 7.0 Hz, 1H), 0.85-0.76 (m, 2H), 0.75-0.70 (m, 2H).

[0234] Compound 078 was prepared in a manner similar to Scheme 2 and obtained as a white solid (10.5 mg, 22.46 umol, 29.08% yield, 100% purity). LCMS: Rt=0.338 min, m / z=468.3 (M+H + ) 1 H NMR (400 MHz, chloroform-d) δ = 12.33 (br s,J=0.8Hz,1H),8.22(s,1H),7.77(s,1H),7.69(td,J=1.4,7.9Hz,1H),7.63 (td,J=1.3,7.8Hz,1H),7.51(t,J=7.8Hz,1H),7.45(d,J=1.5Hz,1H),7.32(d, J=7.4Hz,1H),7.12(dd,J=1.5,7.8Hz,1H),5.12-5.10(m,4H),3.78(td,J=3.0 ,5.8Hz,1H),3.07(s,3H),2.87(s,3H),1.92-1.67(m,4H),0.87-0.69(m,4H).

[0235] Compound 097 was prepared in a manner similar to Scheme 2 and obtained as a brown solid (19 mg, 42.36 umol, 49.04% yield and 100% purity). LCMS: Rt=0.783 min, m / z=449.3 (M+H + ) 1 H-NMR: (400MHz, chloroform-d) δ = 12.42-12.13 (m, 1H), 8.28 (d, J = 7.4Hz, 2H), 7.42-7.35 (m, 2H), 7.3 4-7.29(m,2H),7.09-6.99(m,3H),5.16(s,2H),5.00(s,2H),4.07(q,J=6.9Hz,2H),3.34(br d, J=7.1Hz, 2H), 1.39 (t, J=7.0Hz, 3H), 1.30 (t, J=7.1Hz, 3H).

[0236] Compound 100 was prepared in a manner similar to Scheme 2 and obtained as a white solid (21.1 mg, 43.90 umol, 34.58% yield and 95.8% purity). LCMS: Rt = 0.394 min, m / z = 461.1 (M+H + ) 1H NMR: (400MHz, chloroform-d)δ=12.25(br s,1H),8.26(s,2H),7.39(d,J=1.3Hz,1H),7.37-7.30(m,2H),7.25-7.17(m,2H),7.08-7.00(m,2H),5.14(br s,2H),4.99(s,2H),3.83-3.67(m,1H),3.42-3.25(m,2H),1.31(br t,J=6.9Hz,3H),0.84-0.78(m,2H),0.78-0.72(m,2H).

[0237] Compound 103 was prepared in a manner similar to Scheme 2 and obtained as a white solid (17.3 mg, 37.71 umol, 44.18% yield, 99.3% purity). LCMS: Rt = 0.376 min, m / z = 456.5 (M+H + )1H NMR (400MHz, chloroform-d) δ = 8.44-8.33 (m, 2H), 7.85 (s, 1H), 7.76 (d, J = 8.0Hz, 1 H),7.63(d,J=7.6Hz,1H),7.55-7.49(m,1H),7.34(d,J=7.8Hz,1H),7.05( d,J=7.8Hz,1H),7.00(s,1H),5.23(s,2H),5.01(s,2H),4.06(q,J=6.9Hz ,2H),3.35(q,J=6.7Hz,2H),1.36(t,J=6.9Hz,3H),1.30(t,J=7.0Hz,3H).

[0238] Compound 170 was prepared in a manner similar to Scheme 2 and obtained as a white solid (34.3 mg, 82.69 umol, 27.45% yield, 98% purity). LCMS: Rt = 0.357 min, m / z = 407.0 (M+H + ) 1 H NMR: (400MHz, chloroform-d) δ = 8.27 (s, 1H), 8.23 ​​(s, 1H), 7.70 (d, J = 7.9Hz, 1H), 7.60 (dd, J = 1.1, 3.7Hz, 1H), 7.38 (dd, J = 1.1, 5.1Hz, 1H), 7 .11(dd,J=3.8,5.1Hz,1H),7.09-7.04(m,2H),4.91(s,2H),4.19(q,J=6.9Hz,2H),3.03(s,3H),2.89(s,3H),1.55(t,J=6.9Hz,3H).

[0239] Compound 177 was prepared in a manner similar to Scheme 2 and obtained as a white solid (20.7 mg, 44.52 umol, 40.77% yield). H-NMR: (400 MHz, chloroform-d) δ = 8.34 (s, 1H), 8.26 (s, 1H), 7.49 (s, 1H), 7.39-7.34 (m, 1H), 7.31-7.28 (m, 2H), 7.21 (s, 1H), 7.00-6.95 (m, 1H), 6.93 (s, 1H), 5.16 (s, 2H), 4.94 (s, 2H), 4.04-3.94 (m, 3H), 3.28 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 6.9 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H).

[0240] Solution 3

[0241]

[0242] LiBH4 (184.03 mg, 8.45 mmol, 10 equivalents) was added to a solution of compound 1 (500 mg, 844.96 umol, 1 equivalent) in MeOH (10 mL) in a 100 ml round-bottom flask (100 mL). The mixture was stirred at 20 ° C for 12 hours. The reaction mixture was poured into a saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (100 mL x3), and the combined organic phases were dried and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 0: 0 to 1: 1). Compound 2 (87 mg, 154.33 umol, 18.26% yield) was obtained as a white solid. LCMS: Rt = 0.633 min, m / z = 564.1 (M + H + ).

[0243] To a solution of compound 2 (87 mg, 154.33 umol, 1 eq.) in DCM (2 mL) was added MnO2 (268.34 mg, 3.09 mmol, 20 eq.) The mixture was stirred at 30°C for 2 hours.

[0244] After the reaction was completed, the mixture was filtered and the filtrate was concentrated to give a crude product. The residue was purified by preparative-TLC (PE: EtOAc = 1: 1). Compound 3 (57 mg, 101.47 umol, 65.75% yield) was obtained as a white solid. 1H NMR: (chloroform-d): δ10.10(1H,br s),8.21(2H,br d,J=13.5Hz),7.78-8.03(1H,m),7.29-7.46(3H,m),6.89-7.22(4H,m),5.63-5.99(2H,m),5.16-5.44(2H,m) ,3.93-4.34(2H,m),3.38-3.70(2H,m),3.04-3.28(3H,m),1.22-1.41(3H,m),0.61-1.02(2H,m),-0.07(9H,br s)

[0245] To 100 single-necked bottles containing compound 3 (57mg, 101.47umol, 1 equivalent) dissolved in MeOH (2mL), add HOAc (304.69ug, 5.07umol, 0.29uL, 0.05 equivalent) and THF (2M, 152.21uL, 3 equivalents) containing MeNH2, the reaction mixture was stirred at 20°C for 2 hours by a magnetic stirrer. Then, at 0°C, NaBH4 (7.68mg, 202.95umol, 2 equivalents) was added, and the mixture was stirred at 20°C for 1 hour by a magnetic stirrer. After the reaction was complete, the reaction mixture was poured into NH4Cl (10mL), filtered, and the filtrate was concentrated under reduced pressure to obtain residue. Then, the solution was ground in EtOAc and THF (10mL) and collected by filtration, and the filtrate was concentrated under reduced pressure to obtain residue. Compound 4 (57 mg, 98.83 umol, 97.39% yield) was obtained as a yellow oil and used in the next step without further purification. LCMS: Rt = 0.678 min, m / z = 577.2 (M+H + ).

[0246] To a solution of compound 4 (57 mg, 98.83 umol, 1 equiv) in DCM (2 mL) was added TFA (1.26 g, 11.04 mmol, 817.15 uL, 111.68 equiv) in an 8 mL glass bottle. The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (column: Waters xbridge150*25mm 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 34%-64%, 8min), and the purified product was lyophilized. Compound 003 (8.6 mg, 19.26 umol, 19.49% yield and 100% purity) was obtained as a white solid. LCMS: Rt=0.379 min, m / z=447.4 (M+H + ).1H NMR:(chloroform-d):δ11.57-12.23(1H,m),8.08(1H,s),7.68(1H,s),7.28-7.40(5H,m),7.00-7.09(3H,m),4.96(2H,s),4.06(2H,q,J=7.0Hz),3.89(2H,s),3.01(3H,s),2.51(3H,s),1.36(3H,t,J=6.9Hz).

[0247] Compound 005 was prepared in a manner similar to Scheme 3 and obtained as a white solid (16.3 mg, 35.15 umol, 50.55% yield, 99.3% purity). LCMS: Rt=0.387 min, m / z=461.4 (M+H) + 1H NMR (400MHz, chloroform-d) δppm 8.43-8.52(m,1H)8.21-8.25(m,1H)7.26-7.38(m,4H)7.25(s,1H)7.16-7.20(m,1H)6.98-7.0 7(m,3H)4.94(s,2H)4.00-4.08(m,4H)2.96-3.02(m,3H)2.45-2.52(m,6H)1.31-1.38(m,3H).

[0248] Compound 006 was prepared in a manner similar to Scheme 3 using dimethylamine instead of methylamine and obtained as a white solid (8.3 mg, 17.66 umol, 14.91% yield and 98% purity). LCMS: Rt = 0.346 min, m / z = 461.4 (M + H +). 1H NMR: (chloroform-d): δ 11.94 (1H, br s), 8.07 (1H, s), 7.63 (1H, s), 7.28-7.40 (5H, m), 7.00-7.09 (3H, m), 4.96 (2H, s), 4.07 (2H, q, J = 6.9 Hz), 3.57 (2H, s), 3.01 (3H, s), 2.30 (6H, s), 1.37 (3H, t, J = 7.0 Hz).

[0249] Compound 024 was prepared in a manner similar to Scheme 3 using methyl grignard instead of methylamine and obtained as a white solid (13.8 mg, 28.48 umol, 36.48% yield). LCMS: Rt = 0.399 min, m / z = 485.1 (M+H + ) 1 H-NMR: (400MHz, chloroform-d)δ=12.17(br s,1H),8.33(s,1H),8.27(s,1H),7.00-6.94(m,2H),6.90-6.81(m,3H),5.34(d,J=6.6Hz,1H), 4.95 (s, 2H), 4.07 (q, J = 7.0Hz, 2H), 3.07 (s, 3H), 1.70 (d, J = 6.6Hz, 3H), 1.35 (t, J = 6.9Hz, 3H).

[0250] Compound 025 was prepared in a manner similar to Scheme 3 using ethyl methylamine instead of methylamine and obtained as a white solid (4.1 mg, 8.76 umol, 17.31% yield and 98.8% purity). LCMS: Rt = 0.389 min, m / z = 463.5 (M+H + ) 1H NMR: (400MHz, chloroform-d)δ=12.36(br d,J=1.8Hz,1H),8.31(s,1H),8.26(s,1H),7.41-7.28(m,4H),7.11-7.07(m,2H),7.07-7.02(m,1H),5.20-5.13(m,1H ),5.02-4.88(m,2H),4.11-4.05(m,2H),3.06(s,3H),1.97-1.82(m,2H),1.38(t,J=6.9Hz,3H),1.02(t,J=7.4Hz,3H).

[0251] Compound 026 was prepared in a manner similar to Scheme 3 using methyl pyrimidine instead of methylamine and obtained as a white solid (8.8 mg, 18.86 umol, 29.62% yield). LCMS: Rt = 0.392 min, m / z = 466.9 (M+H + ) 1 H-NMR: (400MHz, chloroform-d) δ = 12.41 (br s, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 7.36 (d, J = 7.6Hz, 1H), 7.15-7.06 (m, 4H), 6.81 (s, 1H), 5.37 (br d,J=6.6Hz,1H),4.97(s,2H),4.10(q,J=7.0Hz,2H),3.07(s,3H),1.71(d,J=6.6Hz,3H),1.40(t,J=7.0Hz,3H).

[0252] Compound 029 was prepared in a manner similar to Scheme 3 using methyl pyrimidine instead of methylamine and obtained as a white solid (6.7 mg, 14.71 umol, 21.54% yield, 100% purity). LCMS: Rt = 0.366 min, m / z = 456.4 (M+H) + 1H NMR (400MHz, chloroform-d) δppm 12.31-12.57(m,1H)8.37(s,1H)8.26-8.31(m,1H)7.84-7.87(m,1H)7.74-7.80(m,1H)7.61-7.66(m,1H)7.50-7.55( m,1H)7.32-7.36(m,1H)7.09(s,2H)5.35-5.43(m,1H)4.94-4.99(m,2H)4.05-4.12(m,2H)3.06-3.09(m,3H)1.72(br d,J=6.63Hz,3H)1.37(t,J=7.00Hz,3H).

[0253] Compound 030 was prepared in a manner similar to Scheme 3 using methyl pyridine instead of methylamine and obtained as a white solid (98.5% purity). LCMS: Rt = 0.393 min, m / z = 464.16 (M+H + ) 1 H NMR: (400MHz, chloroform-d)δ=12.47-12.21(m,1H),8.32(s,1H),8.26(s,1H),7.59-7.58(m,1H),7.55(s,1H),7.42(br d,J=6.1Hz,1H),7.38-7.30(m,3H),7.12-7.05(m,2H),5.37-5.31(m,1H),4.95(s,2H),4.07(q,J=6.8Hz,2H),3.06(s,3H),1.69(br d, J=6.6Hz, 3H), 1.38 (t, J=6.9Hz, 3H).

[0254] Compound 031 was prepared in a manner similar to Scheme 3 using methyl pyrimidine instead of methylamine and obtained as a white solid (16.7 mg, 38.79 umol, 21.75% yield, 100% purity). LCMS: Rt = 0.377 min, m / z = 431.4 (M+H) + 1H NMR (400MHz, chloroform-d) δ=13.07-12.39(m,1H),8.47(s,1H),8.40-8.34(m,1H),7.59-7.51(m,2H),7.46-7.32(m,4 H),7.13-7.05(m,2H),5.54-5.45(m,1H),5.03-4.93(m,2H),4.06(q,J=6.9Hz,2H),3.12-3.08(m,3H),1.76(br d, J=6.5Hz, 3H), 1.37 (t, J=6.9Hz, 3H).

[0255] Compound 070 was prepared in a manner similar to Scheme 3 using methyl pyrimidine instead of methylamine and obtained as a white solid (7 mg, 15.23 umol, 44.22% yield, 98.01% purity). LCMS: Rt = 0.438 min, m / z = 451.2 (M+H) +1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.14-12.36 (m, 1H) 8.45 (d, J = 3.00 Hz, 1H) 8.25 (s, 1H) 7.35 (d, J = 7.50 Hz, 2H) 7.28-7.33 (m, 2H) 7.01-7.11 (m, 3H) 5.90-6.11 (m, 1H) 4.88-5.01 (m, 2H) 4.02-4.12 (m, 2H) 3.05 (s, 3H) 1.80-1.90 (m, 3H) 1.38 (t, J = 6.94 Hz, 3H).

[0256] Solution 4

[0257]

[0258] Pd(OAc)2(329.95mg, 1.47mmol, 0.1 eq.) and DPPF(1.63g, 2.94mmol, 0.2 eq.), TEA(4.46g, 44.09mmol, 6.14mL, 3 eq.) were added to a solution of compound 1(5g, 14.70mmol, 1 eq.) in MeOH(60mL). The mixture was stirred at 80°C under CO(50psi) for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, EtOAc / methanol=100 / 1 to 5 / 1). The purified solution was concentrated under vacuum to give a residue. Compound 2(570mg, 1.78mmol, 12.11% yield) was obtained as a yellow solid. LCMS: Rt=0.504min, m / z=319.9(M+H) +

[0259] LAH (101.61 mg, 2.68 mmol, 1.5 eq.) was added to a 100 mL three-necked flask solution of compound 2 (570 mg, 1.78 mmol, 1 eq.) in 2-MeTHF (10 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 12 hours. After the reaction was completed, Na2SO4·10H2O (3 g) was added to the resulting mixture. Then, the mixture was filtered and the filtrate was concentrated to give a crude product. The residue was purified by column chromatography (SiO2, PE / EtOAc=10 / 1 to 1 / 2). The purified solution was concentrated under vacuum to give a residue. Compound 3 (200 mg, 686.47 umol, 38.46% yield) was obtained as a colorless oil. LCMS: Rt=0.367 min, m / z=292.1 (M+H) +

[0260] To a 100 mL round-bottom flask solution of compound 3 (200 mg, 686.47 umol, 1 eq.) in EtOAc (2 mL) was added HCl / dioxane (4 M, 2 mL, 11.65 eq.). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under vacuum to give a residue. Compound 4 (130 mg, crude, HCl) was obtained as a white solid, which was used in the next step. LCMS: Rt=0.122 min, m / z=161.1 (M-30) +

[0261] To compound 4 (130mg, 570.95umol, 1 equivalent, HCl), compound 5 (148.60mg, 570.95umol, 1 equivalent) in DCM (5mL) solution, add EDCI (164.18mg, 856.43umol, 1.5 equivalents) DMAP (6.98mg, 57.10umol, 0.1 equivalents) and DIPEA (221.37mg, 1.71mmol, 298.35uL, 3 equivalents). The mixture was stirred at 20 ° C for 12 hours. The reaction mixture was poured into water (15mL) and extracted with EtOAc (10mL x3), the combined organic phase was dried and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=10 / 1 to 1 / 4). The purified solution was concentrated under vacuum to obtain a residue. Compound 6 (160 mg, 369.11 umol, 64.65% yield) was obtained as a colorless oil. LCMS: Rt = 0.451 min, m / z = 434.3 (M+H) +

[0262] MnO2 (481.34 mg, 5.54 mmol, 15 eq.) was added to a 8 mL glass bottle solution of compound 6 (160 mg, 369.11 umol, 1 eq.) in DCM (3 mL). The mixture was stirred at 20 ° C for 2 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated to give a crude product. The residue was purified by preparative-TLC (PE / EtOAc=1:1, Rf=0.3), and the purified solution was concentrated under vacuum to give a residue. Compound 7 (120 mg, 278.13 umol, 75.35% yield) was obtained as a colorless oil. LCMS: Rt=0.480 min, m / z=432.3 (M+H) +

[0263] MeNH2(2M, 104.30uL, 3 equivalents) and AcOH(208.78ug, 3.48umol, 1.99e-1uL, 0.05 equivalents) were added to a 50mL round-bottom flask solution of compound 7(30mg, 69.53umol, 1 equivalent) in MeOH(2mL) at 20°C, the mixture was stirred for 2 hours at 20°C, and then NaBH4(5.26mg, 139.06umol, 2 equivalents) was added to the mixture at 0°C. The mixture was stirred for 2 hours at 20°C. After the reaction was complete, the reaction mixture was poured into NH4Cl(5mL) and the temperature was controlled between 10 and 20°C, then Na2CO3(1g) was added to the mixture, the solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. Then, the solution was ground in DCM and MeOH and collected by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water (FA)-ACN]; B%: 18%-48%, 10min), and the purified solution was lyophilized to give a white solid. 004 (21.6 mg, 46.58 umol, 67.00% yield, 96.3% purity) was obtained as a white solid, LCMS: Rt=0.381 min, m / z=447.4 (M+H) + 1H NMR (400 MHz, chloroform-d) δ ppm 8.39-8.48 (m, 1H) 8.22-8.28 (m, 1H) 7.22-7.36 (m, 5H) 7.16-7.20 (m, 1H) 6.97-7.04 (m, 3H) 4.82-4.90 (m, 2H) 4.21-4.32 (m, 2H) 4.02 (q, J = 6.84 Hz, 2H) 2.92-3.01 (m, 3H) 2.48-2.59 (m, 3H) 1.28-1.38 (m, 3H).

[0264] Solution 5

[0265]

[0266] A solution of compound 9 (50mg, 90.96umol, 1 equivalent) in DCM (2mL) was added to an 8mL glass bottle. Then, Et3N (18.41mg, 181.92umol, 25.32uL, 2 equivalents) and acetyl chloride (8.57mg, 109.15umol, 7.79uL, 1.2 equivalents) were added to the above mixture. The mixture was stirred at 20 °C for 12 hours. The mixture was poured into H2O (20mL). The aqueous phase was extracted with EtOAc (20mL x 2). The combined organic matter was dried over Na2SO4 and concentrated under vacuum. This compound was used directly in the next step without any purification. Compound 11 (53mg, 89.57umol, 98.47% yield, purity is not available) was obtained as an off-white solid. LCMS: Rt=0.690min, m / z=474.3(M+H + ).

[0267] To a solution of compound 11 (73 mg, 123.36 umol, 1 eq.) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 109.48 eq.) in a 100 mL round-bottom flask. The mixture was stirred at 20 °C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (column: Phenomenex C18 150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 36%-66%, 8 min). Compound 007 (7.7 mg, 16.02 umol, 12.98% yield, 96% purity) was obtained as a white solid. LCMS: Rt=0.590 min, m / z=462.2 (M+H + ).1H NMR:(chloroform-d):δ12.02(1H,br s),8.10(1H,s),7.48(1H,d,J=1.8Hz),7.29-7.40(4H,m),7.00-7.09(4H,m),4.9 4(2H,s), 4.06(2H,q,J=6.9Hz), 3.03(3H,s), 2.36(3H,s), 1.37(3H,t,J=6.9Hz).

[0268] Compound 009 was prepared in a manner similar to Scheme 5 and isolated as a white solid (31 mg, 62.33 umol, 37.82% yield, 95.8% purity). LCMS: Rt = 0.393 min, m / z = 477.4 (M+H) +1H NMR (400 MHz, CHLOROFORM-d) δ=12.51-11.86 (m, 1H), 8.28 (s, 1H), 8.23 ​​(s, 1H), 7.33-7.26 (m, 2H), 7.25-7.22 (m, 1H), 7.21-7.19 (m, 1H), 7.02 (br d, J=1.5 Hz, 2H), 6.97-6.94 (m, 1H), 5.51-5.48 (m, 2H), 4.87 (s, 2H), 4.03-3.96 (m, 2H), 2.98 (s, 3H), 2.17-2.14 (m, 3H), 1.33-1.27 (m, 3H).

[0269] Solution 6

[0270]

[0271] EDCI (2.21 g, 11.53 mmol, 1.5 eq.) and DMAP (93.88 mg, 768.46 umol, 0.1 eq.) were added to a 40 mL glass bottle containing a solution of compound 1 (2.85 g, 7.68 mmol, 1 eq.) and compound 2 (2 g, 7.68 mmol, 1 eq.) in DCM (20 mL), and the mixture was stirred at 20 ° C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE: EtOAc = 2: 1). Compound 3 (3.8 g, 6.20 mmol, 80.72% yield) was obtained as a white solid. LCMS: Rt = 0.610 min, m / z = 612.6 (M + H + ).

[0272] To a 250 mL hydrogenation bottle containing a solution of compound 3 (3.7 g, 6.04 mmol, 1 eq.) in MeOH (40 mL), Pd(OAc)2 (271.20 mg, 1.21 mmol, 0.2 eq.), TEA (1.83 g, 18.12 mmol, 2.52 mL, 3 eq.) and DPPF (669.67 mg, 1.21 mmol, 0.2 eq.) were added and the mixture was stirred at 80 °C under CO (50 psi) for 12 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 0: 0 to 2: 1). Compound 4 was obtained as a yellow solid. LCMS: Rt = 0.605 min, m / z = 592.3 (M + H + ).

[0273] To a solution of compound 4 (200 mg, 337.98 umol, 1 equiv.) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 39.96 equiv.), and the mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (neutral conditions, column: Welch Xtimate C18150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 44%-74%, 2 min), the purified product was lyophilized and 008 (140 mg, 302.46 umol, 89.49% yield, 99.7% purity) was obtained as a white solid. LCMS: Rt=0.531 min, m / z=462.2 (M+H + ). 1 H NMR: 1H NMR (400 MHz, chloroform-d) δ = 12.35-12.10 (m, 1H), 8.56 (d, J = 1.1 Hz, 1H), 8.23 ​​(s, 1H), 7.99 (s, 1H), 7.41-7.29 (m, 4H), 7.11-7.02 (m, 3H), 5.00 (s, 2H), 4.07 (q, J = 6.8 Hz, 2H), 3.98 (s, 3H), 3.04 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H).

[0274] Solution 7

[0275]

[0276] To a solution of compound 1 (5 g, 14.70 mmol, 1 eq.) in MeOH (60 mL) was added Pd(OAc)2 (329.95 mg, 1.47 mmol, 0.1 eq.), DPPF (1.63 g, 2.94 mmol, 0.2 eq.) and TEA (4.46 g, 44.09 mmol, 6.14 mL, 3 eq.). The mixture was stirred at 80 °C under CO (50 psi) for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=100 / 1 to 5 / 1). The purified solution was concentrated under vacuum to give a residue. Compound 2 (1 g, 3.13 mmol, 21.30% yield) was obtained as a yellow solid. LCMS: Rt=0.485 min, m / z=219.7 (M-100) +1H NMR (400MHz, chloroform-d) δppm 11.59-12.41 (m, 1H) 8.56 (s, 1H) 7.85-7.90 (m, 1H) 7.23-7.26 (m, 1H) 4.65-4.69 (m, 2H) 4.03 (s, 3H) 2.81 (s, 3H) 1.49-1.54 (m, 9H)

[0277] To a 100 mL round-bottom flask solution of compound 2 (500 mg, 1.57 mmol, 1 eq.) in EtOAc (3 mL) was added HCl / dioxane (4 M, 6 mL, 15.33 eq.). The mixture was stirred at 20 °C for 2 hours. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under vacuum to give a residue. Compound 3 (450 mg, crude, HCl) was obtained as a white solid, which was used in the next step. LCMS: Rt=0.225 min, m / z=220.2 (M+H) +

[0278] To compound 3 (450mg, 1.76mmol, 1 equivalent, HCl), compound 4 (458.02mg, 1.76mmol, 1 equivalent) in DCM (8mL) 100mL round-bottom flask solution add EDCI (506.06mg, 2.64mmol, 1.5 equivalents), DMAP (21.50mg, 175.99umol, 0.1 equivalents) and DIPEA (1.14g, 8.80mmol, 1.53mL, 5 equivalents). The mixture was stirred at 20°C for 12 hours. The reaction mixture was poured into water (50mL) and extracted with EtOAc (50mL x3), the combined organic phase was dried and concentrated under vacuum to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenexluna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 51%-81%, 10 min), and the purified solution was lyophilized to give a white solid. 010 (500 mg, 1.07 mmol, 60.83% yield, 98.8% purity) was obtained as a white solid, LCMS: Rt=0.502 min, m / z=462.3 (M+H) +1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.59-8.64 (m, 1H) 7.92 (d, J = 7.25 Hz, 1H) 7.40 (s, 1H) 7.33-7.36 (m, 2H) 7.28-7.32 (m, 2H) 7.01-7.09 (m, 3H) 5.03 (s, 2H) 4.06-4.10 (m, 2H) 4.05 (s, 3H) 2.99-3.04 (m, 3H) 1.37 (t, J = 6.94 Hz, 3H).

[0279] Compound 066 was prepared in a manner similar to Scheme 7, with the additional step of reducing the ester as follows: the esterified compound was dissolved in 2-MeTHF (5 mL), and LAH (16.45 mg, 433.38 umol, 2 equivalents) was added at 0 ° C. After the reaction was completed, Na2SO4·10H2O (5 g) was added to the resulting mixture. Then, the mixture was filtered and the filtrate was concentrated to give a crude product. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 49%-79%, 10 min), and the purified solution was lyophilized to give a white solid. 066 (6.1 mg, 13.92 umol, 6.42% yield, 98.9% purity) was obtained as a white solid. LCM S: Rt=0.458min, m / z=434.3(M+H) + 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.25-8.29 (m, 1H) 7.29-7.40 (m, 4H) 7.24-7.26 (m, 1H) 7.12-7.15 (m, 1H) 7.00-7.08 (m, 3H) 5.05-5.10 (m, 2H) 4.95-4.98 (m, 2H) 4.03-4.10 (m, 2H) 2.99-3.02 (m, 3H) 1.37 (t, J = 7.00 Hz, 3H).

[0280] Compound 069 was prepared in a manner similar to Scheme 7, with the additional step of reducing the ester as follows: the esterified compound was dissolved in MeOH (2 mL), and LiBH4 (18.41 mg, 844.96 umol, 5 equivalents) was added at 0 ° C. The reaction mixture was poured into a saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (10 mL x3), the combined organic phases were dried and concentrated under vacuum to give a residue. The residue was purified by preparative-TLC (PE: EtOAc = 1: 1). Compound 2 (30 mg, 53.22 umol, 31.49% yield) was obtained as a white oil. LCMS: Rt = 0.553 min, m / z = 446.2 (M + H +).

[0281] Solution 8

[0282]

[0283] Compound 1 (200.00 mg, 645.44 umol, 1 equivalent) and compound 2 (166.32 mg, 1.94 mmol, 3 equivalents) were dissolved in dioxane (5 mL) and H in a 40 mL bottle O (0.5 mL), and CsCO (630.89 mg, 1.94 mmol, 3 equivalents) and Pd (dppf) Cl CHCl (52.71 mg, 64.54 umol, 0.1 equivalent) were added, and the reaction mixture was stirred at 100 ° C under N for 12 hours. After the reaction was completed and cooled to room temperature, the reaction mixture was filtered with EtOAc (50 mL), and the filtrate was concentrated on a rotary evaporator to obtain a crude product. The crude product was purified by preparative-TLC (PE: EtOAc = 1: 1, Rf = 0.7). The purified solution was concentrated in vacuo to give compound 3 (68 mg, 215.54 umol, 33.39% yield) as a yellow oil. LCMS: Rt = 0.405 min, m / z = 316.2 (M+H) +

[0284] Ozone (11.26 mg, 234.56 umol, 1 equivalent) was bubbled into a three-necked flask (100 mL) containing a solution of compound 3 (74.00 mg, 234.56 umol, 1 equivalent) in MeOH (8 mL) and DCM (8 mL) at -78 ° C under 15 psi for 20 min, then the mixture was purged with nitrogen for 10 min, PPh3 (123.04 mg, 469.12 umol, 2 equivalents) was dissolved in DCM (8 mL) and added to the reaction mixture at -78 ° C for 10 min. The mixture was stirred at 20 ° C for 1 hour. After the reaction was completed, the mixture was concentrated to obtain a residue. The residue was purified by preparative-TLC (SiO2, PE / EtOAc=1:1). The purified solution was concentrated in vacuo to obtain compound 4 (35 mg, 110.25 umol, 47.00% yield) as a white solid. 1H NMR (400MHz, chloroform-d) δ=11.07(s,1H),9.23(s,1H),8.39(s,1H),5.81(s,2H),3.73-3.67(m,2H),3.30-3.23(m,1H),1.40-1.35(m,2H),1.20-1.14(m,2H),1.01-0.95(m,2H),0.00 -0.01(m,9H)

[0285] AcOH (662.08ug, 11.03umol, 6.31e-1uL, 0.1 equivalent) and THF (2M, 330.75uL, 6 equivalents) containing MeNH2 were added to a round-bottom flask (50mL) containing a solution of compound 4 (35.00mg, 110.25umol, 1 equivalent) in MeOH (2mL), and the mixture was stirred at 20°C for 2 hours. Then, NaBH3CN (10.39mg, 165.38umol, 1.5 equivalents) was added to the reaction mixture at 0°C. The mixture was stirred at 20°C for 3 hours. After the reaction was complete, the reaction mixture was poured into NH4Cl (0.1mL), filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The solution was then triturated in dichloromethane (10 mL) and collected by filtration, and the filtrate was concentrated under reduced pressure to give Compound 5 (60 mg, crude) as a yellow oil, which was used in the next step. LCMS: Rt=0.573 min, m / z=333.0 (M+H) +

[0286] To a round-bottom flask (50 mL) containing a solution of compound 5 (60 mg, 180.44 umol, 1 eq.) and compound 6 (46.96 mg, 180.44 umol, 1 eq.) in DCM (3 mL), EDCI (51.89 mg, 270.66 umol, 1.5 eq.) and DMAP (2.20 mg, 18.04 umol, 0.1 eq.) were added. The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative-TLC (SiO2, PE / EtOAc=1:1). The purified solution was concentrated in vacuo to give compound 7 (30 mg, 52.20 umol, 28.93% yield) as a colorless oil. LCMS: Rt=0.482 min, m / z=575.6 (M+H) +

[0287] TFA (770.00 mg, 6.75 mmol, 500.00 uL, 129.38 equiv) was added to a round-bottom flask (100 mL) containing a solution of compound 7 (30.00 mg, 52.20 umol, 1 equiv) in DCM (0.5 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated to give a residue. The residue was basified to pH 8 with Et3N. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 26%-56%, 9min). The purified solution was lyophilized to give 011 (7 mg, 15.24 umol, 29.21% yield, 96.8% purity) as a white solid. LCMS: Rt=0.402min, m / z=445.1(M+H) + 1H NMR (400MHz, chloroform-d) δ = 9.03 (brs, 1H), 8.20 (br s,1H),7.41-7.34(m,2H),7.33-7.30(m,2H),7.09-7.00(m,3H),5.29-5.23(m,2H),4.07 (q,J=6.9Hz,2H),3.11(s,3H),2.46-2.37(m,1H),1.40-1.35(m,3H),1.33-1.26(m,4H).

[0288] Compound 016 was prepared in a manner similar to Scheme 8 and obtained as a white solid (45.2 mg, 99.11 umol, 95.34% yield and 98% purity). LCMS: Rt=0.404 min, m / z=447.2 (M+H + ) 1H NMR: (400 MHz, CHLOROFORM-d) δ = 12.15 (br s, 1H), 9.01 (s, 1H), 8.19 (s, 1H), 7.47-7.42 (m, 2H), 7.36-7.30 (m, 4H), 7.11-7.07 (m, 1H), 5.12 (s, 2H), 3.87-3.68 (m, 1H), 3.06 (s, 3H), 2.84 (s, 3H), 0.85-0.79 (m, 2H), 0.78-0.72 (m, 2H).

[0289] Solution 9

[0290]

[0291] In a 250mL three-necked bottle, K2CO3 (8.27g, 59.82mmol, 2 equivalents) and KI (496.53mg, 2.99mmol, 0.1 equivalent) were added to a solution of compound 1 (5g, 29.91mmol, 1 equivalent) and compound 2 (3.62g, 29.91mmol, 1 equivalent) in acetone (50mL). The mixture was stirred at 60 ° C for 12 hours. The reaction mixture was poured into water (200mL) and extracted with EtOAc (200mL x3), and the combined organic phase was dried and concentrated under vacuum to obtain a residue. Compound 1-allyloxy-2,3-dimethyl-4-nitro-benzene (6.02g, 29.05mmol, 97.12% yield) was obtained as a yellow oil, which was used in the next step without further purification. LCMS: Rt=0.475min, m / z=208.4(M+H + )

[0292] Subsequently, a solution of compound 3 (6.02 g, 29.05 mmol, 1 eq.) in EtOH (60 mL) and H2O (12 mL) was added to a 500 mL three-necked flask. Fe (8.11 g, 145.25 mmol, 5 eq.), NH4Cl (15.54 g, 290.51 mmol, 10 eq.) were added to the mixture in batches at 20 °C. The mixture was stirred at 70 °C for 2 hours. The reaction mixture was filtered through a celite pad, the filtrate was purified to saturated water (500 mL) at 0 °C and extracted with EtOAc (500 mL x 3), the combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated to give a crude product. The residue was purified by silica gel chromatography (PE: EtOAc = 10: 1). Compound 4 (4.42 g, 24.93 mmol, 85.82% yield, purity not available) was obtained as a brown solid. LCMS: Rt=0.207 min, m / z=178.4 (M+H+ ) 1 H NMR (400MHz, chloroform-d) δ = 6.63 (d, J = 8.5Hz, 1H), 6.55 (d, J = 8.5Hz, 1H), 6.07 (ddt, 1H), 5.41 (qd, J = 1.7, 17.3Hz ,1H),5.25(qd,J=1.5,10.5Hz,1H),4.45(td,J=1.5,5.2Hz,2H),3.62(br.s,2H),2.21(s,3H),2.12(s,3H).

[0293] A solution of compound 4 (3.3 g, 18.62 mmol, 1 equivalent) in DCM (30 mL) and HOAc (3 mL) was added to a 100 mL three-necked round-bottom flask. Then, DCM (5 mL) containing Br2 (2.98 g, 18.62 mmol, 959.82 uL, 1 equivalent) was added dropwise to the above mixture at 0 ° C. The mixture was stirred for 3 hours at 0 ° C. The reaction mixture was poured into saturated NaHCO3 aqueous solution (300 mL) in batches. The aqueous phase was extracted with EtOAc (200 mL x 2). The combined organic phases were washed with H2O (200 mL x3), brine (200 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 90: 1). Compound 5 (1.26 g, 3.89 mmol, 20.87% yield, 79% purity) was obtained as a brown solid. LCMS: Rt=0.422 min, m / z=256.3, 258.3 (M+H + ). 1 H NMR (400MHz, chloroform-d) δ = 6.88 (s, 1H), 6.11-6.00 (m, 1H), 5.41 (dd, J = 1.0, 17.3Hz, 1H), 5.27 (dd, J = 0.8, 10.5Hz, 1H), 4.43 (d, J = 5.1Hz, 2H), 3.81 (br s, 2H), 2.17 (d, J = 4.6Hz, 6H).

[0294] To a 100 mL single-necked round-bottom flask containing a solution of compound 5 (1 g, 3.90 mmol, 1 eq.) in HOAc (20 mL) and H2O (2 mL) was added NaNO2 (538.77 mg, 7.81 mmol, 2 eq.) at 5 °C, and the mixture was stirred at 20 °C for 12 h. The mixture was poured into water (100 mL) and adjusted to pH = 8 with saturated NaHCO3 solution, extracted with EtOAc (100 mL X2), and the combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give a crude product. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1). Compound 6 (389 mg, 1.46 mmol, 37.30% yield, purity not available) was obtained as a light brown solid. LCMS: Rt=0.434min, m / z=267.0,269.0(M+H + ). 1 HNMR (400 MHz, CHLOROFORM-d) δ = 8.14 (br s, 1H), 7.28 (s, 1H), 6.14-6.04 (m, 1H), 5.47-5.40 (m, 1H), 5.30 (dd, J = 1.3, 10.5 Hz, 1H), 4.61-4.52 (m, 2H), 2.47 (s, 3H).

[0295] To a 20 mL single-necked round-bottom flask containing a solution of compound 6 (276 mg, 1.03 mmol, 1 eq.) in 2-MeTHF (5 mL) was added NaH (82.65 mg, 2.07 mmol, 60% purity, 2 eq.) at 0°C, the mixture was stirred at 0°C for 0.5 h, then SEM-Cl (258.39 mg, 1.55 mmol, 274.30 uL, 1.5 eq.) was added dropwise, the mixture was warmed to 20°C and stirred at 20°C for 2 h. After the reaction was completed, the mixture was poured into a saturated NH4Cl (50 mL) solution at 0°C, and extracted with EtOAc (50 mL x 2), the combined organic phases were washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated to give a crude product. The residue was purified by silica gel column chromatography (PE / EtOAc=10 / 1). Compound 7 (267 mg, 671.90 umol, 65.03% yield, purity not available) was obtained as a brown oil. LCMS: Rt = 0.600 min, m / z = 396.8, 398.8 (MH + )

[0296] Compound 7 (206mg, 518.39umol, 1 equivalent) is added to the solution in 2-MeTHF (5mL) in 25mL serpentine tube.Then, at -70 ℃ under N2 atmosphere, hexane (2.5M, 414.72uL, 2 equivalents) containing n-BuLi is added to the above mixture, and the mixture is stirred for 1 hour at -70 ℃.Then, DMF (41.68mg, 570.23umol, 43.87uL, 1.1 equivalents) is added to the above mixture, and the mixture is stirred for 1h at -70 ℃ under N2 atmosphere.The mixture is poured into ice-NH4Cl (saturated, 50mL) and stirred for 1min.Water is extracted with EtOAc (40mL x 2).The organic phase merged is washed with brine (60mL), through anhydrous Na2SO4, dried, filtered and concentrated in a vacuum. The residue was purified by preparative-TLC (PE:EtOAc=10:1). Compound 8 (30 mg, 86.58 umol, 16.70% yield, purity not available) was obtained as a light brown solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=10.39 (s, 1H), 8.10 (s, 1H), 7.69 (s, 1H), 6.15-6.08 (m, 1H), 6.03 (s, 2H), 5.47 (dd, J=1.5, 17.1 Hz, 1H), 5.32 (dd, J=1.3, 10.5 Hz, 1H), 4.67 (d, J=5.1 Hz, 2H), 3.54-3.48 (m, 3H), 2.59 (s, 3H), 0.90-0.80 (m, 2H), -0.08 (s, 9H).

[0297] At 20 ℃, in 100mL single round-bottom flask, MeOH (1mL) containing compound 8 (45mg, 129.87umol, 1 equivalent) is added to THF (2M, 194.81uL, 3 equivalents) and HOAc (779.91ug, 12.99umol, 7.43e-1uL, 0.1 equivalent) containing MeNH2. The mixture is stirred for 3 hours at 20 ℃. Then, at 0 ℃, the mixture is added to NaBH4 (9.83mg, 259.74umol, 2 equivalents). The mixture is stirred for 1 hour at 0 ℃. After the reaction is completed, the reaction mixture is poured into NH4Cl (0.1mL), filtered, and the filtrate is concentrated under reduced pressure to obtain a residue. Then, the solution is ground in EtOAc and THF (50mL) and collected by filtration, and the filtrate is concentrated under reduced pressure to obtain a residue. Purification is not required and used for the next step. Compound 9 (53 mg, 127.09 umol, 97.86% yield, 86.7% purity) was obtained as a light brown solid. LCMS: Rt=0.359 min, m / z=362.4 (MH + ) 1 H NMR (400MHz, chloroform-d) δ = 8.01 (s, 1H), 7.12 (s, 1H), 6.21-6.11 (m, 1H), 5.99 (s, 2H), 5.49 (dd, J = 1.5, 17.3Hz, 1H), 5.34 (dd, J = 1.4, 1 0.5Hz,1H),4.68-4.60(m,2H),4.20-4.16(m,2H),3.64-3.54(m,2H),2.58(s,1H),2.54(s,3H),1.03-0.84(m,2H),0.00(s,9H).

[0298] A solution of compound 9 (53 mg, 127.09 umol, 86.7% purity, 1 eq) in DCM (2 mL) was added to a 50 mL single-necked round-bottom flask, compound 10 (33.08 mg, 127.09 umol, 1 eq), EDCI (36.55 mg, 190.64 umol, 1.5 eq) and DMAP (1.55 mg, 12.71 umol, 0.1 eq). The reaction mixture was stirred at 20 ° C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative-TLC (PE: EtOAc = 2: 1). Compound 11 (40 mg, 66.25 umol, 52.12% yield, purity not available) was obtained as a light brown solid. LCMS: Rt = 0.645 min, fragment Ms: m / z = 486.8 (M + H + )

[0299] To a solution of compound 11 (40 mg, 66.25 umol, 1 eq.) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 203.87 eq.) in a 100 mL single bottle. The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the residue. The residue was basified with Et3N to a pH of about 8. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 60%-90%, 10 min) and lyophilized. White solid compound 12 (20 mg, 42.24 umol, 63.75% yield, purity not available) was obtained. LCMS: Rt=0.551 min, m / z=474.5 (M+H + )

[0300] Pd(PPh3)4 (7.32 mg, 6.34 umol, 0.2 equiv) and 1,3-dimethylhexahydropyrimidine-2,4,6-trione (14.84 mg, 95.03 umol, 3 equiv) were added to a solution of compound 12 (15 mg, 31.68 umol, 1 equiv) in DCM (1 mL) in an 8 mL bottle under N2. The mixture was stirred at 20 ° C under N2 for 5 hours. The reaction mixture was filtered and the filtrate was concentrated to give a crude product. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 34%-64%, 8min) and lyophilized. 015 (4.6 mg, 10.52 umol, 33.20% yield, 99.1% purity) was obtained as a white solid. LCMS: Rt=0.463min, m / z=434.3(M+H + ) 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.04 (s, 1H), 7.40-7.28 (m, 4H), 7.10-7.01 (m, 3H), 6.93 (s, 1H), 4.89 (s, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.01 (s, 3H), 2.50 (s, 3H), 1.37 (br t, J = 6.8 Hz, 3H).

[0301] Compound 036 was prepared in a manner similar to Scheme 9 and obtained as a white solid (15.1 mg, 36.00 umol, 27.20% yield, 100% purity). LCMS: Rt=0.482 min, m / z=420.3 (M+H) +1H NMR (400MHz, chloroform-d) δ = 8.02 (s, 1H), 7.58 (d, J = 8.6Hz, 1H), 7.39-7.28 (m, 4H), 7.09-7.00 (m, 3H ), 6.87-6.81 (m, 1H), 5.02 (s, 2H), 4.03 (q, J = 6.9Hz, 2H), 3.14 (s, 3H), 1.34 (t, J = 6.9Hz, 3H).

[0302] Solution 10

[0303]

[0304] NH2NH2.H2O (1.43 g, 28.51 mmol, 1.39 mL, 3.5 equivalents) was added to a solution of compound 1 (1.8 g, 8.14 mmol, 1 equivalent) in DMSO (20 mL) in a 100 mL three-necked flask. The mixture was stirred at 120 ° C for 12 hours. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL x 2), the combined organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated under vacuum to give a residue. The combined aqueous phase was acidified to a pH of about 4 with a 1N HCl aqueous solution and discarded into a waste bucket. The residue was purified by silica gel chromatography (PE: EtOAc = 0: 0 to 1: 1). Compound 2 (695 mg, 3.23 mmol, 39.68% yield) was obtained as a white solid. LCMS: Rt=0.361min, m / z=216.8(M+H + ).

[0305] NaH (193.91 mg, 4.85 mmol, 60% purity, 1.5 equivalents) was added to a solution of compound 1 (695 mg, 3.23 mmol, 1 equivalent) in THF (10 mL) in a 100 mL three-necked flask at 0 ° C, the mixture was stirred for 1 hour at 0 ° C, then SEM-Cl (808.32 mg, 4.85 mmol, 858.09 uL, 1.5 equivalents) was added to the reactant at 0 ° C, and the reaction mixture was stirred for 2 hours at 20 ° C. The reaction mixture was poured into saturated NH4Cl aqueous solution (100 mL), the mixture was extracted with EtOAc (500 mLx3), and the combined organic phase was dried and concentrated under vacuum to obtain a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 0: 0 to 1: 1). Compound 3 (787 mg, 2.28 mmol, 70.52% yield) was obtained as a yellow oil. LCMS: Rt=0.556min, m / z=344.04(M+H + ).

[0306] To a 50 mL single-necked round-bottom flask containing a solution of compound 3 (787 mg, 2.28 mmol, 1 eq.) and compound 4 (1.23 g, 3.42 mmol, 1.15 mL, 1.5 eq.) in dioxane (10 mL) and H2O (1 mL), K2CO3 (630.02 mg, 4.56 mmol, 2 eq.) and Pd(PPh3)2Cl2 (239.97 mg, 341.89 umol, 0.15 eq.) were added. The mixture was stirred at 100°C for 12 hours.

[0307] After the reaction is completed and cooled to room temperature, the reaction mixture is diluted with saturated potassium fluoride solution (100mL) and stirred at 20 ° C for 2h. Then, the mixture is filtered, the filtrate is extracted with EtOAc (100mL × 3), the organic phases combined are washed with brine (150mL × 3), dried over anhydrous Na2SO4, and concentrated to give a crude product. The residue is purified by silica gel chromatography (PE: EtOAc = 0: 0 to 10: 1). Compound 5 (680mg, 2.02mmol, 88.67% yield) is obtained as a yellow oil. 1 H NMR: 1 H NMR (chloroform-d): δ8.00 (1H, s), 7.65 (1H, dd, J = 4.9 and 8.8 Hz), 6.99 (1H, t, J = 9.1 Hz), 5.74 (2H, s), 4.42-4.72 (2H, m), 4.13 (2H, q, J = 7.1 Hz), 3.49-3.58 (2H, m), 1.40 (3H, t, J = 7.0 Hz), 0.84 (3H, s), -0.06 (9H, s)

[0308] To a solution of compound 5 (500 mg, 1.49 mmol, 1 eq.) in DCM (5 mL) was added TFA (7.70 g, 67.53 mmol, 5 mL, 45.44 eq.) in a 100 ml single-mouth round-bottom flask. The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 0: 0 to 2: 1). Compound 6 (250 mg, 1.40 mmol, 94.43% yield) was obtained as a yellow oil. LCMS: Rt = 0.307 min, m / z = 179.1 (M + H + ).

[0309] HOAc (471.87ug, 7.86umol, 4.49e-1uL, 0.01 equivalent) and THF (2M, 1.18mL, 3 equivalents) containing MeNH2 are added to the 100mL single-necked bottle containing compound 6 dissolved in MeOH (2mL), and the reaction mixture is stirred at 20 DEG C for 2 hours by a magnetic stirrer. Then, NaBH4 (59.45mg, 1.57mmol, 2 equivalents) is added at 0 DEG C, and the mixture is stirred at 20 DEG C for 1 hour by a magnetic stirrer. After the reaction is complete, the reaction mixture is poured into NH4Cl (10mL), filtered, and the filtrate is concentrated under reduced pressure to obtain residue. Then, the solution is ground in EtOAc and THF (10mL) and collected by filtration, and the filtrate is concentrated under reduced pressure to obtain residue. Compound 7 is obtained as a yellow oil. LCMS: Rt=0.412min, m / z=194.0(M+H + ).

[0310] EDCI (197.93 mg, 1.03 mmol, 1.5 eq) and DMAP (8.41 mg, 68.83 umol, 0.1 eq) were added to a 40 mL glass bottle containing a solution of compound 7 (133 mg, 688.33 umol, 1 eq) and compound 8 (179.15 mg, 688.33 umol, 1 eq) in DCM (5 mL), and the mixture was stirred at 20 ° C for 12 hours. The mixture was neutralized with Na2CO3 at 20 ° C and filtered, and the filtrate was concentrated to give a crude product. The residue was purified by preparative-TLC (SiO2, PE: EtOAc = 3: 1) to give 017 (7.4 mg, 16.48 umol, 2.39% yield, 97% purity) as a colorless oil, LCMS: Rt = 0.543 min, m / z = 436.4 (M + H + ).HNMR: (400MHz, chloroform-d)δ=12.27-11.82(m,1H),8.07(s,1H),7.67(dd,J=4.5, 8.8Hz,1H),7.39-7.28(m,4H),7.08-6.99(m,3H),6.98-6.89(m,1H),6.41(br d,J=7.0Hz,1H),4.26-3.85(m,2H),3.28-2.76(m,3H),1.95(dd,J=4.1,7.3Hz,3H),1.36(t,J=6.9Hz,3H).

[0311] Compound 116 was prepared in a manner similar to Scheme 10 and obtained as a white solid (11.0 mg, 25.26 umol, 24.40% yield, 100% purity). LCMS: Rt = 0.735 min, m / z = 435.9 (M+H + )1H NMR (400 MHz, CHLOROFORM-d) δ=8.18(s,1H),7.41-7.33(m,2H),7.33-7.28(m,3H),7.08-7.00(m,3H),6.79(dd,J=8.1,9.4Hz,1H),6.48(d,J=6.6Hz,1H),4.14-3.99(m,2H),2.76(s,3H),1.84-1.78(m,3H),1.37(t,J=6.9Hz,3H).

[0312] Solution 11

[0313]

[0314] EDCI (151.15 mg, 788.46 umol, 1 eq.) and DMAP (6.42 mg, 52.56 umol, 0.1 eq.) were added to a round-bottom flask (50 mL) containing a solution of compound 1 (152.57 mg, 525.64 umol, 1 eq.) and compound 2 (100 mg, 525.64 umol, 1 eq.) in DCM (5 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 22%-52%, 9min). The purified solution was lyophilized to give compound 3 (85 mg, 173.13 umol, 32.94% yield, 94.2% purity) as a white solid. LCMS: Rt=0.415min, m / z=462.9(M+H) +

[0315] Compound 3 (85 mg, 183.79 umol, 1 equivalent) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 um); mobile phase: [ACN / IPA (0.1% NH3H2O)]; B%: 45%-45%, A 2.8; 22 min), and the solution was concentrated to remove the organic solvent. The residual aqueous solution was freeze-dried to obtain 034 (31.6 mg, 68.33 umol, 37.18% yield, 100% purity) as a white solid and 035 (32.5 mg, 69.78 umol, 37.97% yield, 99.3% purity) as a white solid.

[0316] Data of 034: LCMS: Rt=0.730 min, m / z=463.2 (M+H) + SFC: Rt = 0.591 min 1H NMR (400 MHz, chloroform-d) δ = (400 MHz, chloroform-d) δ = 12.18-11.92 (m, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 7.41-7.34 (m, 1H), 7.22-7.19 (m, 1H), 7.14-7.09 (m, 1H), 7.09-7.02 (m, 2 H),6.90-6.84(m,1H),6.48-6.39(m,1H),3.78-3.72(m,1H),2.92-2.87(m,3H), 2.86-2.79(m,3H),1.87(d,J=7.3Hz,3H),0.84-0.76(m,2H),0.75-0.65(m,2H).

[0317] Data of 035: LCMS: Rt=0.731 min, m / z=463.2 (M+H) + SFC: Rt = 0.851 min 1H NMR (400 MHz, chloroform-d) δ = (400 MHz, chloroform-d) δ = 8.32 (s, 1H), 8.26 (s, 1H), 7.41-7.34 (m, 1H), 7.21 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.09-7.02 (m, 2H), 6.90-6.84 (m, 1H), 6.47-6.39 (m, 1H), 3.80-3.71 (m, 1H), 2.90 (s, 3H), 2.85-2.80 (m, 3H), 1.89-1.85 (m, 3H), 0.83-0.77 (m, 2H), 0.74-0.64 (m, 2H).

[0318] Compounds 042 and 043 were prepared in a manner similar to Scheme 11. Data of 042: (17 mg, 39.04 umol, 34.00% yield), LCMS: Rt = 0.522 min, m / z = 435.9 (M+H + ), 1 H NMR: H NMR (400 MHz, chloroform-d) δ = 11.84 (br s, 1H), 8.00 (s, 1H), 7.33-7.21 (m, 5H), 7.11 (dd, J = 1.4, 9.8 Hz, 1H), 7.01-6.93 (m, 3H), 6.44 (br d, J = 6.9 Hz, 1H), 4.06-3.92 (m, 2H), 2.70 (s, 3H), 1.72 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 6.9 Hz, 3H). Data of 043: (15.5 mg, 35.59 umol, 31.00% yield), LCMS: Rt = 0.519 min, m / z = 435.9 (M+H + ) 1 H NMR: (400 MHz, CHLOROFORM-d) δ = 8.10 (s, 1H), 7.42-7.30 (m, 5H), 7.21 (br d, J = 9.4 Hz, 1H), 7.09-7.02 (m, 3H), 6.61-6.46 (m, 1H), 4.15-4.01 (m, 2H), 2.80 (s, 3H), 1.82 (d, J = 7.1 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H).

[0319] Compounds 044 and 045 were prepared in a manner similar to Scheme 11. Data of 044: (8.2 mg, 18.20 umol, 39.36% yield and 96% purity), LCMS: Rt = 0.689 min, m / z = 433.2 (M+H+). 1H NMR: (chloroform-d): δ 12.18-12.47 (1H, m), 8.99 (1H, s), 8.20 (1H, s), 7.29-7.41 (4H, m), 7.02-7.12 (3H, m), 5.68 (1H, q, J = 7.2 Hz), 4.00-4.15 (2H, m), 2.95 (3H, s), 2.83 (3H, s), 2.01 (3H, d, J = 7.3 Hz), 1.38 (3H, t, J = 6.9 Hz). Data of 045: (9.8 mg, 21.53 umol, 46.55% yield and 95% purity), LCMS: Rt=0.619 min, m / z=433.2 (M+H+). 1H NMR: (chloroform-d): δ12.07-12.66 (1H, m), 8.99 (1H, s), 8.20 (1H, s), 7.28-7.39 (4H, m), 6.97-7.12 (3H, m), 5.68 (1H, q, J=7.0 Hz), 4.02-4.14 (2H, m), 2.95 (3H, s), 2.83 (3H, s), 2.01 (3H, br d, J=7.3 Hz), 1.38 (3H, br t, J=7.0 Hz).

[0320] Compounds 049 and 050 were prepared in a manner similar to Scheme 11. Data of 049: (13.1 mg, 28.84 umol, 34.64% yield, 95% purity), LCMS: Rt=0.409 min, m / z=433.4 (M+H + ). 1 H NMR: (400 MHz, chloroform-d) δ = 12.09 (br s, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.43-7.30 (m, 4H), 7.11-7.02 (m, 3H), 6.51-6.41 (m, 1H), 4.18-4.00 (m, 2H), 2.87 (s, 3H), 2.84-2.78 (m, 1H), 1.88 (d, J = 7.3 Hz, 3H), 1.45-1.34 (m, 3H). Data of 050: (13.8 mg, 31.17 umol, 37.45% yield, 97% purity), LCMS: Rt = 0.406 min, m / z = 433.6 (M+H + ). 1H NMR: (400MHz, chloroform-d)δ=12.00(br s,1H),8.22(s,1H),8.14(s,1H),7.33-7.20(m,4H),7.01-6.93(m,3H),6.36(q,J=7.1Hz,1H ), 4.07-3.91 (m, 2H), 2.77 (s, 3H), 2.73 (s, 3H), 1.78 (d, J = 7.1Hz, 3H), 1.29 (t, J = 6.9Hz, 3H).

[0321] Compounds 051 and 052 were prepared in a manner similar to Scheme 11. Data of 051: (11.1 mg, 25.79 umol, 22.20% yield), LCMS: Rt = 0.613 min, m / z = 431.3 (M+H+). 1H NMR: (chloroform-d): δ 12.01-12.32 (1H, m), 9.07-9.18 (1H, m), 8.42-8.50 (1H, m), 8.27 (1H, s), 7.32-7.46 (2H, m), 7.01-7.25 (5H, m), 6.51 (1H, br d, J = 6.5 Hz), 3.78 (1H, br s), 2.84 (3H, s), 1.90 (3H, br d, J = 7.1 Hz), 0.74-0.88 (4H, m). Data of 051: (12.8 mg, 29.73 umol, 25.60% yield), LCMS: Rt = 0.613 min, m / z = 431.3 (M + H +). 1H NMR: (chloroform-d): δ 12.05-12.31 (1H, m), 8.96-9.32 (1H, m), 8.22-8.57 (2H, m), 7.44 (1H, s), 7.31-7.40 (2H, m), 7.18-7.25 (2H, m), 7.01-7.12 (2H, m), 6.39-6.62 (1H, m), 3.78 (1H, br d, J = 3.0 Hz), 2.84 (3H, s), 1.90 (3H, br d,J=7.1Hz),0.80-0.88(4H,m).

[0322] Compounds 056 and 057 were prepared in a manner similar to Scheme 11. Data of 056: LCMS: Rt = 0.586 min, m / z = 420.3 (M+H + ). 1H NMR: (400 MHz, chloroform-d) δ = 12.11-11.98 (m, 1H), 9.12 (s, 1H), 8.45 (br s, 1H), 8.25 (s, 1H), 7.78-7.72 (m, 1H), 7.49-7.30 (m, 5H), 7.12-7.05 (m, 1H), 4.43 (br d, J = 6.5 Hz, 2H), 2.94 (br s, 3H), 1.89 (br d, J = 6.5 Hz, 3H), 1.38 (br d, J = 6.0 Hz, 3H). Data of 057: LCMS: Rt = 0.586 min, m / z = 420.3 (M+H + ) 1 H NMR: (400MHz, chloroform-d)δ=12.09-11.94(m,1H),9.05(s,1H),8.40-8.34(m,1H),8.18(s,1H),7.67(br d,J=6.3Hz,1H),7.42-7.22(m,5H),7.04-6.97(m,1H),4.46-4.20(m,2H),2.86(br s,3H),1.82(br d,J=6.3Hz,3H),1.34-1.27(m,3H).

[0323] Compounds 058 and 059 were prepared in a manner similar to Scheme 11. Data of 058: LCMS: Rt = 0.696 min, m / z = 418.2 (M+H + ).H-NMR: (400MHz, chloroform-d) δ=12.00-11.76(m,1H),8.13(s,1H),7.78-7.73(m,1H),7.42-7.28(m,5H),7.21-7.15(m,1H),7.07-7.00(m,3H),6.58-6.50(m,1H),4.14-3.99(m,2H),2.76(s,3H),1.84-1.80(m,3H),1.37(t,J=7.0Hz,3H). Data of 059: LCMS: Rt=0.692min, m / z=418.1(M+H +).H-NMR: (400 MHz, CHLOROFORM-d) δ=11.85-11.78 (m, 1H), 8.04 (s, 1H), 7.70-7.65 (m, 1H), 7.33-7.21 (m, 5H), 7.13-7.07 (m, 1H), 6.99-6.92 (m, 3H), 6.46 (q, J=6.9 Hz, 1H), 4.06-3.91 (m, 2H), 2.68 (s, 3H), 1.74 (d, J=7.1 Hz, 3H), 1.29 (t, J=7.0 Hz, 3H).

[0324] Compounds 123 and 124 were prepared in a manner similar to Scheme 11. Data for 123: LCMS: Rt = 0.615 min, m / z = 434.3 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 13.04-11.60 (m, 1H), 8.39-8.10 (m, 2H), 7.90-7.66 (m, 1H), 7.51-7.28 (m, 4H), 7.14-7.01 (m, 1H), 6.43 (br d, J = 6.6 Hz, 1H), 4.72-4.18 (m, 2H), 2.99-2.63 (m, 6H), 1.80-1.61 (m, 3H), 1.35-1.17 (m, 3H) Data of 124: LCMS: Rt = 0.614 min, m / z = 434.3 (M+H + ) 1 H NMR: (400 MHz, CHLOROFORM-d) δ = 12.95-11.89 (m, 1H), 8.33-8.18 (m, 2H), 7.85-7.71 (m, 1H), 7.48-7.31 (m, 4H), 7.12-7.05 (m, 1H), 6.54-6.17 (m, 1H), 4.66-4.23 (m, 2H), 2.93-2.66 (m, 6H), 1.90-1.72 (m, 3H), 1.33 (br s, 3H).

[0325] Compounds 094 and 095 were prepared in a manner similar to Scheme 11. Data of 094: LCMS: Rt = 0.129 min, m / z = 449.2 (M+H + ). 1H NMR: (chloroform-d) δ: ppm 1.38 (t, J = 6.94 Hz, 3H) 1.68 (d, J = 6.63 Hz, 3H) 3.06 (s, 3H) 4.07 (q, J = 7.13 Hz, 2H) 4.95 (s, 2H) 5.32 (q, J = 6.59 Hz, 1H) 7.01-7.12 (m, 3H) 7.31 (d, J = 7.38 Hz, 2H) 7.33-7.41 (m, 2H) 8.20-8.33 (m, 2H) 12.22-12.42 (m, 1H). 095 data: LCMS: Rt = 0.134 min, m / z = 449.2 (M+H + ). 1 H NMR:(chloroform-d)δ:ppm 1.38(t,J=7.00Hz,3H)1.51-1.60(m,5H)1.66-1.81(m,2H)3.52(s,3H)3.57-3.63(m,1H)3.83-3.92(m,1H) 4.11-4.16(m,1H)4.94(s,1H)7.00-7.08(m,1H)7.25-7.29(m,2H)7.30(d,J=1.13Hz,1H)7.32-7.37(m,3H).

[0326] Compounds 123 and 124 were prepared in a manner similar to Scheme 11. Data for 123 (34.09 mg, 76.44 umol, 36.82% yield and 97.2% purity): LCMS: Rt=0.615 min, m / z=434.3 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 13.04-11.60 (m, 1H), 8.39-8.10 (m, 2H), 7.90-7.66 (m, 1H), 7.51-7.28 (m, 4H), 7.14-7.01 (m, 1H), 6.43 (br d, J = 6.6 Hz, 1H), 4.72-4.18 (m, 2H), 2.99-2.63 (m, 6H), 1.80-1.61 (m, 3H), 1.35-1.17 (m, 3H). Data of 124 (30.89 mg, 69.62 umol, 33.53% yield and 97.7% purity): LCMS: Rt = 0.614 min, m / z = 434.3 (M+H + ) 1H NMR: (400 MHz, CHLOROFORM-d) δ = 12.95-11.89 (m, 1H), 8.33-8.18 (m, 2H), 7.85-7.71 (m, 1H), 7.48-7.31 (m, 4H), 7.12-7.05 (m, 1H), 6.54-6.17 (m, 1H), 4.66-4.23 (m, 2H), 2.93-2.66 (m, 6H), 1.90-1.72 (m, 3H), 1.33 (br s, 3H).

[0327] Compounds 159 and 160 were prepared in a manner similar to Scheme 11. Data of 159 (7.4 mg, 16.50 umol, 37.00% yield): LCMS: Rt = 0.648 min, m / z = 449.1 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.19 (s, 1H), 8.35-8.25 (m, 1H), 8.18 (s, 1H), 7.45-7.20 (m, 5H), 6.99-6.96 (m, 2H), 6.40 (q, J = 6.8 Hz, 1H), 5.06 (s, 2H), 4.07-3.92 (m, 2H), 2.74 (s, 3H), 1.81 (d, J = 7.1 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H). Data of 160 (8.4 mg, 18.73 umol, 42.00% yield): LCMS: Rt = 0.646 min, m / z = 449.1 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.46-11.91 (m, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.40 (s, 5H), 6.98 (s, 2H), 6.39 (d, J = 7.0 Hz, 1H), 5.05 (s, 2H), 4.07-3.92 (m, 2H), 2.74 (s, 3H), 1.81 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 6.9 Hz, 3H).

[0328] Solution 12

[0329]

[0330] SeO2 (544.94 mg, 4.91 mmol, 534.26 uL, 5 equiv) was added to a 40 mL glass bottle containing a solution of compound 1 (350 mg, 982.23 umol, 1 equiv) in dioxane (5 mL), and the mixture was stirred at 60 ° C for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give a crude product. The residue was purified by silica gel chromatography (PE: EtOAc = 10: 1). Compound 2 (360 mg, 972.14 umol, 98.97% yield, purity not available) was obtained as a light brown solid. LCMS: Rt = 0.559 min, m / z = 369.8, 371.8 (M + H + ). 1 HNMR (400 MHz, CHLOROFORM-d) δ = 10.20 (s, 1H), 8.73 (s, 1H), 6.11 (s, 2H), 3.63-3.58 (m, 2H), 2.92 (s, 3H), 0.94-0.86 (m, 2H), -0.05 (s, 9H).

[0331] To a 100 mL single-necked round-bottom flask containing a solution of compound 2 (325 mg, 877.63 umol, 1 eq.) in MeOH (7 mL) was added LiBH4 (115 mg, 5.28 mmol, 6.02 eq.) at 0 ° C., and the mixture was stirred at 0 ° C. for 0.5 h. After the reaction was completed, the reaction mixture was quenched with saturated NH4Cl aqueous solution (50 mL) at 0 ° C. The mixture was extracted with EtOAc (50 mL X 2), the combined organic phases were dried over Na2SO4, and concentrated in vacuo to give a crude product. The residue was purified by silica gel chromatography (PE: EtOAc = 1: 1). Compound 3 (257 mg, 676.44 umol, 77.08% yield, 98% purity) was obtained as a white solid. LCMS: Rt = 0.131 min, m / z = 226.0, 228.0 (M + H + ).

[0332] To a 50 mL single-necked round-bottom flask containing a solution of compound 3 (257 mg, 690.24 umol, 1 eq.) in DCM (5 mL) at 0°C, imidazole (117.47 mg, 1.73 mmol, 2.5 eq.) and TBSCl (208.07 mg, 1.38 mmol, 169.16 uL, 2 eq.) were added, and the mixture was stirred at 20°C for 12 h. f=0.21) was detected by TLC (PE: EtOAc = 10: 1, plate 1). The mixture was filtered and the filtrate was concentrated to give a crude product. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1). Compound 4 (320 mg, 657.63 umol, 95.28% yield, purity not available) was obtained as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ=8.44 (s, 1H), 6.07 (s, 2H), 5.07 (s, 2H), 3.66-3.54 (m, 2H), 2.77 (s, 3H), 0.97 (s, 9H), 0.91-0.87 (m, 2H), 0.16 (s, 6H), -0.05 (s, 9H)

[0333] To a solution of compound 4 (320 mg, 657.63 umol, 1 eq.) and compound 5 (176.18 mg, 1.32 mmol, 2 eq.) in dioxane (4 mL) and H2O (0.4 mL) was added K2CO3 (181.78 mg, 1.32 mmol, 2 eq.) and Pd(dppf)Cl2.CH2Cl2 (53.70 mg, 65.76 umol, 0.1 eq.) under N2. The mixture was stirred at 100 °C under N2 for 16 hours. The reaction mixture was filtered through a diatomaceous earth pad. The combined filter cake was washed with EtOAc / methanol = 10 / 1, 10 mL x 5. The combined filtrate was concentrated to give a crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 10: 1). Compound 6 (190 mg, 438.06 umol, 66.61% yield, purity not available) was obtained as a colorless oil.

[0334] A solution of compound 6 (190 mg, 438.06 umol, 1 equivalent) in DCM (12 mL) and MeOH (12 mL) was treated with ozone (21.03 mg, 438.06 umol, 1 equivalent) for 30 min (15 psi) in a 100 mL three-necked round-bottom flask at -78 ° C, and the mixture was then purged with nitrogen for 0.5 h, PPh3 (229.79 mg, 876.11 umol, 2 equivalents) was dissolved in DCM (12 mL) and added dropwise to the mixture at -78 ° C. The mixture was warmed to 20 ° C and stirred at 20 ° C for 1 h. After the reaction was complete, the mixture was concentrated to give a crude product. The residue was purified by silica gel chromatography (PE: EtOAc = 10: 1). Compound 7 (140 mg, 321.32 umol, 73.35% yield, purity not available) was obtained as a light brown solid. 1HNMR (400MHz, chloroform-d) δ = 10.81 (s, 1H), 8.64 (s, 1H), 6.07 (s, 2H), 5.24 (br s,2H),3.56-3.49(m,2H),3.02(s,3H),1.06(s,9H),0.96-0.87(m,2H),0.26(s,6H),0.17(d,J=12.6Hz,1H),0.00(s,9H).

[0335] At 20 ℃, in 50mL single round-bottom flask, MeOH (2mL) containing compound 7 (140mg, 321.32umol, 1 equivalent) is added to THF (2M, 481.98uL, 3 equivalents) and HOAc (1.93mg, 32.13umol, 1.84uL, 0.1 equivalent) containing MeNH2. The mixture is stirred at 20 ℃ for 3 hours. Then, at 0 ℃, the mixture is added to NaBH4 (24.31mg, 642.63umol, 2 equivalents). The mixture is stirred at 20 ℃ for 1 hour. After the reaction is completed, the reaction mixture is poured into NH4Cl (0.1mL), filtered, and the filtrate is concentrated under reduced pressure to obtain residue. Then, the solution is ground in EtOAc and THF (80mL) and collected by filtration, and the filtrate is concentrated under reduced pressure to obtain compound 8 (150mg, thick) in a light brown oil. LCMS: Rt=0.446min, m / z=452.1(M+H + )

[0336] A solution of compound 8 (50 mg, 94.28 umol, 85% purity, 1 eq) in DCM (1 mL) was added to an 8 mL bottle, compound 9 (24.54 mg, 94.28 umol, 1 eq), EDCI (27.11 mg, 141.43 umol, 1.5 eq) and DMAP (1.15 mg, 9.43 umol, 0.1 eq). The reaction mixture was stirred at 20 ° C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative-TLC (PE: EtOAc = 2: 1). Compound 10 (47 mg, 67.82 umol, 71.93% yield, purity not available) was obtained as an off-white solid. LCMS: Rt = 0.559 min, m / z = 694.0 (M + H + )

[0337] To a 50mL single-necked round-bottom flask containing a solution of compound 10 (42mg, 60.61umol, 1 equivalent) in HCl / dioxane (4M, 2mL, 132.00 equivalents). The mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated to give a crude product. The crude product was basified with Et3N to a pH of about 8 to 9. The residue was purified by preparative-HPLC (column: Watersxbridge 150*25mm 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 27%-57%, 11min), and lyophilized. 037 (5.2mg, 11.43umol, 18.86% yield and 98.6% purity) was obtained as a white solid. LCMS: Rt=0.389min, m / z=449.5 (M+H + ) 1 H NMR (400MHz, chloroform-d)δ=13.15(br s,1H),8.59(s,1H),7.41-7.37(m,2H),7.33-7.30(m,2H),7.11-7.05(m,3H),7.01(s,1H),5.88(br s,1H),5.38(br s,2H),5.11(s,2H),4.08(q,J=6.9Hz,2H),3.14(s,1H),3.12(s,3H),1.39(t,J=6.9Hz,3H).

[0338] Compound 040 was prepared in a manner similar to Scheme 12 and isolated as a white solid (6.8 mg, 13.68 umol, 25.30% yield and 99.6% purity). LCMS: Rt = 0.416 min, m / z = 495.5 (M+H + ) 1 H NMR (400MHz, chloroform-d) δ = 12.09 (br s, 1H), 8.11 (s, 1H), 7.30-7.28 (m, 1H), 7.20 (s, 2H), 7.15 (br s, 2H), 6.80 (br d,J=8.4Hz,1H),5.03(s,2H),5.01(s,2H),4.39(br s,1H),3.68(brd,J=3.1Hz,1H),2.99(s,3H),2.77(s,3H),0.77-0.68(m,2H),0.65(br s,2H).

[0339] Compound 041 was prepared in a manner similar to Scheme 12 and isolated as a white solid (13 mg, 27.26 umol, 35.75% yield and 100% purity). LCMS: Rt = 0.375 min, m / z = 477.4 (M+H + ) 1 H NMR (400MHz, chloroform-d) δ = 12.29 (br s, 1H), 8.18 (s, 1H), 7.44 (br d, J = 7.4Hz, 2H), 7.37-7.29 (m, 4H), 7.12-7.06 (m, 1H), 5.10-5.08 (m, 4H), 4.52 (br s,1H),3.81-3.74(m,1H),3.06(s,3H),2.84(s,3H),0.85-0.72(m,4H).

[0340] Compound 053 was prepared in a manner similar to Scheme 12 and isolated as a white solid (30.9 mg, 70.95 umol, 39.93% yield and 99.3% purity). LCMS: Rt = 0.388 min, m / z = 433.4 (M+H + ) 1 H NMR (400 MHz, CHLOROFORM-d) δ = 12.09 (br s, 1H), 8.15 (s, 1H), 7.41-7.27 (m, 4H), 7.09-7.01 (m, 3H), 5.07 (s, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 2.79 (s, 3H), 1.37 (t, J = 6.9 Hz, 3H).

[0341] Compound 054 was prepared in a manner similar to Scheme 12 and isolated as a white solid (7.3 mg, 16.70 umol, 20.56% yield and 99.4% purity). LCMS: Rt = 0.443 min, m / z = 435.3 (M+H + ) 1 H NMR (400 MHz, CHLOROFORM-d) δ = 12.27 (br s, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.40-7.34 (m, 2H), 7.33-7.28 (m, 2H), 7.09-7.02 (m, 3H), 5.43 (s, 2H), 4.07 (q, J = 6.9 Hz, 2H), 3.31 (s, 3H), 2.56 (s, 3H), 1.39-1.35 (m, 3H).

[0342] Compound 079 was prepared in a manner similar to Scheme 12 and isolated as a white solid (6 mg, 12.97 umol, 18.34% yield, 100% purity). LCMS: Rt = 0.390 min, m / z = 463.1 (M+H + ) 1 H NMR (400 MHz, CHLOROFORM-d) δ = 12.46 (s, 1H), 8.31-8.23 (m, 1H), 7.41-7.34 (m, 2H), 7.33-7.28 (m, 2H), 7.13-7.00 (m, 3H), 5.39-5.24 (m, 1H), 5.10 (s, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.06 (s, 3H), 2.89 (s, 3H), 1.72 (br s, 3H), 1.38 (t, J = 6.9 Hz, 3H).

[0343] Compound 117 was prepared in a manner similar to Scheme 12 and isolated as a white solid (15 mg, 34.68 umol, 18.05% yield). LCMS: Rt = 0.743 min, m / z = 433.2 (M+H + ) 1 H NMR: (400MHz, chloroform-d)δ=12.33-11.81(m,1H),9.04(br s,1H),8.34(br s,1H),8.19(s,1H),7.36-7.21(m,4H),7.04-6.90(m,3H),6.19-5.97(m,1H),3.99(br dd,J=7.2,17.4Hz,2H),2.76-2.66(m,3H),2.41-2.10(m,2H),1.33-1.26(m,3H),1.17-1.11(m,3H).

[0344] Solution 13

[0345]

[0346] Compound 2 (200 mg, 652.58 umol, 1 eq.), EDCI (187.65 mg, 978.86 umol, 1.5 eq.), DMAP (7.97 mg, 65.26 umol, 0.1 eq.) were added to a 40 mL flask containing compound 1 (169.84 mg, 652.58 umol, 1 eq.) dissolved in DCM (5 mL), and the reaction mixture was stirred at 20 ° C for 16 hours by a magnetic stirrer. The reaction mixture was concentrated under vacuum to give a residue. The crude product was purified by column chromatography on silica gel, eluted with PE: EtOAc = 0: 1 (desired compound = 0.5), and the purified solution was concentrated in vacuo to give a colorless oil. Compound 3 (348 mg, 615.17 umol, 94.27% yield, 97% purity) was obtained as a colorless oil. LCMS: Rt=0.484min, m / z=549.4(M+H + )

[0347] m-CPBA (111.00 mg, 546.72 umol, 85% purity, 3 equivalents) was slowly added to a 50 mL single-mouth round-bottom flask containing a solution of 3 (100 mg, 182.24 umol, 1 equivalent) in DCM (2 mL) at 0 ° C, and the mixture was stirred at 20 ° C for 1 hour by a magnetic stirrer. After the reaction was completed, the reaction mixture was quenched with Na2SO3 (20 mL) and extracted with EtOAc (20 mLx3), and the combined organic phases were dried and concentrated under vacuum to give a residue. The crude product was purified by preparative-HPLC (column: Waters xbridge150*25mm 10um; mobile phase: [water (NH4HCO3)-CAN]; B%: 45%-75%, 8min). After preparative-HPLC purification, the eluate was concentrated to remove the organic solvent. The residual aqueous solution was freeze-dried to give a white solid. Compound 4 (42 mg, 73.63 umol, 40.40% yield, 99% purity) was obtained as a white solid. LCMS: Rt=0.699 min, m / z=565.1 (M+H + )

[0348] 40 mL of a solution containing compound 4 (50 mg, 88.54 umol, 1 eq.) in Ac2O (5.45 g, 53.38 mmol, 5 mL, 602.95 eq.) was stirred at 100 °C under N2 for 16 hours. The reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml). The separated organic layer was dried over (Na2SO4) and evaporated to dryness to give a crude product. The crude product was purified by preparative-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 62%-92%, 8 min). After preparative-HPLC purification, the eluate was concentrated to remove the organic solvent. The residual aqueous solution was lyophilized to give a white solid. Compound 5 (10 mg, 16.48 umol, 18.61% yield) was obtained as a white solid. 1 H-NMR: (400MHz, chloroform-d)δ=9.15(s,1H),8.24(s,1H),7.44(s,2H),7.38-7.34(m,2H),7.20-7.13(m,2H),7.08(br t,J=8.4Hz,1H),5.99-5.98(m,2H),5.52-5.38(m,4H),3.65-3.60(m,2H),2.91(s, 3H),2.19(s,3H),2.06(s,2H),1.45-1.41(m,3H),0.95-0.91(m,3H),0.00(s,9H).

[0349] To a 100 mL single-necked round-bottom flask containing compound 5 (7 mg, 11.54 umol, 1 eq.) dissolved in H2O (1 mL), THF (1 mL) and EtOH (1 mL), LiOH.H2O (2.42 mg, 57.68 umol, 5 eq.) was added, and the reaction mixture was stirred at 20 ° C. for 1 hour by a magnetic stirrer. After the reaction was completed, the mixture was extracted with EtOAc (25 mL X3), and the combined organic phases were washed with brine (50 ml), dried over anhydrous Na2SO4, and concentrated to give a crude product. The crude product was used in the next step without purification. Compound 6 (30 mg, crude) was obtained as a white solid. LCMS: Rt=0.471 min, m / z=565.5 (M+H + )

[0350] Compound 6 (30 mg, 53.12 umol, 1 equivalent) was dissolved in DCM (2 mL) in a 100 mL single-necked round-bottom flask, and TFA (1.54 g, 13.51 mmol, 1 mL, 254.24 equivalent) was added at 0 ° C. The reaction mixture was stirred at 20 ° C for 1 hour by a magnetic stirrer. After the reaction was completed, the solution was removed under reduced pressure using a rotary evaporator to obtain a crude product. The crude product was purified by preparative-HPLC (column: Phenomenex C18 150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-58%, 8min). After preparative-HPLC purification, the eluate was concentrated to remove the organic solvent. The residual aqueous solution was lyophilized to obtain a brown solid. 039 (2.8 mg, 6.44 umol, 12.13% yield) was obtained as a brown solid, LCMS: Rt = 0.574 min, m / z = 435.3 (M+H + ) 1 H-NMR: (400 MHz, CHLOROFORM-d) δ = 12.87-12.67 (m, 1H), 9.21 (br s, 1H), 8.43 (s, 1H), 7.40-7.36 (m, 2H), 7.33-7.31 (m, 2H), 7.11-7.04 (m, 3H), 5.23-5.16 (m, 2H), 5.13 (s, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.11 (s, 3H), 1.38 (s, 3H).

[0351] Solution 14

[0352]

[0353] To a 250 ml three-necked flask containing a solution of compound 1 (370 mg, 746.66 umol, 1 eq.) in 2-MeTHF (30 mL) at 0° C. under N2, NaH (44.80 mg, 1.12 mmol, 60% purity, 1.5 eq.) was added, and the mixture was stirred at 0° C. under N2 for 1 hour. Then, SEM-Cl (149.38 mg, 895.99 umol, 158.58 uL, 1.2 eq.) was added dropwise at 0° C. under N2, and the mixture was stirred at 20° C. under N2 for 12 hours by a magnetic stirrer. After the reaction was completed, the reaction mixture was poured into a saturated NH4Cl (100 mL) solution at room temperature, and extracted with EtOAc (100 mL×3), and the combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give a crude product. The residue was purified by flash silica chromatography ( 4g Silica flash column, eluent 0 to 28% EtOAc / PE gradient, 40 mL / min). Compound 2 (430 mg, 687.12 umol, 92.03% yield) was obtained as a colorless oil. LCMS: Rt=0.637 min, m / z=626.3 (M+Na + )

[0354] Pd / C (200 mg, 31.96 umol, 1 eq.) was added to a solution of compound 2 (200 mg, 319.59 umol, 1 eq.) in MeOH (20 mL) under N2, and the mixture was stirred at 20 ° C. under H2 for 1 hour (644.23 ug, 319.59 umol, 1 eq.) (15 psi). After the reaction was completed, the mixture was filtered under N2 atmosphere, and the filtrate was concentrated to give a crude product. The residue was purified by preparative-TLC (SiO2, PE / EtOAc=1 / 1). Compound 3 (102 mg, 190.41 umol, 59.58% yield) was obtained as a yellow oil. LCMS: Rt=0.590 min, m / z=536.3 (M+H + )

[0355] K2CO3 (41.28 mg, 298.69 umol, 2 equiv) and MeI (63.59 mg, 448.03 umol, 27.89 uL, 3 equiv) were added to an 8 mL glass bottle containing a solution of compound 3 (80 mg, 149.34 umol, 1 equiv) in DMF (2 mL). The mixture was stirred at 50 ° C for 12 hours. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 mL x3), and the combined organic phases were dried and concentrated under vacuum to give a residue. The residue was purified by preparative-TLC (SiO2, PE / EtOAc=5 / 1). Compound 4 (45 mg, 81.86 umol, 54.81% yield) was obtained as a colorless oil. LCMS: Rt=0.625 min, m / z=550.3 (M+H + )

[0356] TFA (3.08 g, 27.01 mmol, 2 mL, 329.97 equiv) was added to a 100 ml round-bottom flask containing a solution of compound 4 (45 mg, 81.86 umol, 1 equiv) in DCM (2 mL) at 20 ° C. The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (column: Watersxbridge 150*25mm 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 8min). Then, the purified solution was lyophilized to give the product. 060 (15.4 mg, 36.71 umol, 44.85% yield, 100% purity) was obtained as a white solid. LCMS: Rt=0.491 min, m / z=420.3 (M+H + ) 1 H NMR: (400 MHz, CHLOROFORM-d) δ = 11.60 (brs, 1H), 8.06 (s, 1H), 7.77-7.66 (m, 1H), 7.44-7.39 (m, 1H), 7.35 (d, J = 1.4 Hz, 1H), 7.33-7.27 (m, 3H), 7.27-7.18 (m, 2H), 7.11-7.05 (m, 1H), 7.01-6.93 (m, 1H), 5.19 (s, 2H), 4.06-3.98 (m, 2H), 3.32 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H).

[0357] Solution 15

[0358]

[0359] NBS (7.11 g, 39.95 mmol, 1 eq.) was added to a solution of compound 1 (5 g, 39.95 mmol, 4.55 mL, 1 eq.) in DCM (50 mL), and the mixture was stirred at 20 ° C for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3), and the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=10 / 1), and the purified solution was concentrated under vacuum to give compound 2 (6 g, 29.41 mmol, 73.60% yield) as an orange oil. LCMS: Rt=0.386 min, m / z=204.1 (M+H) +1H NMR: (400MHz, chloroform-d) δ=7.17-7.11 (m, 1H), 6.40-6.36 (m, 1H), 3.83-3.59 (m, 2H), 2.12-2.07 (m, 3H)

[0360] NIS (6.62 g, 29.41 mmol, 1 eq.) was added to a solution of compound 2 (6 g, 29.41 mmol, 1 eq.) in MeCN (60 mL) at 0 ° C, and the mixture was stirred at 20 ° C for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=10 / 1), and the purified solution was concentrated under vacuum to give compound 3 (6 g, 18.19 mmol, 61.84% yield) as a brown oil, LCMS: Rt=0.515 min, m / z=329.8 (M+H) + 1H NMR: (400MHz, chloroform-d) δ=7.69-7.65 (m, 1H), 4.21 (br s, 2H), 2.19-2.17 (m, 3H)

[0361] To a solution of compound 3 (6 g, 18.19 mmol, 1 eq.) in AcOH (60 mL) and H2O (6 mL) was added NaNO2 (1.25 g, 18.19 mmol, 1 eq.) at 5 °C, and the mixture was stirred at 20 °C for 2 hours. The mixture was poured into water (100 mL) and adjusted to pH = 8 with saturated Na2CO3 brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give a crude product. The residue was purified by column chromatography (SiO2, PE / EtOAc=10 / 1 to 5 / 1), and the purified solution was concentrated under vacuum to give compound 4 (4.65 g, 13.64 mmol, 75.00% yield) as a brown solid, 1H NMR: (400 MHz, chloroform-d) δ = 8.35-8.28 (m, 1H), 7.84 (br d, J = 5.8 Hz, 1H)

[0362] To a solution of compound 4 (4.65 g, 13.64 mmol, 1 eq.) in 2-MeTHF (100 mL) was added NaH (818.30 mg, 20.46 mmol, 60% purity, 1.5 eq.) at 0°C, the mixture was stirred at 0°C for 1 hour, then SEM-Cl (3.41 g, 20.46 mmol, 3.62 mL, 1.5 eq.) was added to the reactant at 0°C, and the reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was poured into a saturated NH4Cl aqueous solution (500 mL), the mixture was extracted with EtOAc (500 mLx3), the combined organic phases were dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=5 / 1), the purified solution was concentrated under vacuum to give compound 5 (6.2 g, crude) as a brown oil. LCMS: Rt=0.662min, m / z=354.8(M+H) +

[0363] To a glass bottle (75 mL) containing a solution of compound 5 (960 mg, 2.04 mmol, 1 eq.) in MeOH (20 mL) was added Pd(OAc)2 (45.74 mg, 203.74 umol, 0.1 eq.), DPPF (225.90 mg, 407.49 umol, 0.2 eq.) and TEA (412.33 mg, 4.07 mmol, 567.17 uL, 2 eq.). The mixture was stirred at 40 °C under CO (30 psi) for 12 hours. LCMS (5-95AB / 0.8 min) showed 70% of compound 5 remaining. The reaction mixture was filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=10 / 1 to 5 / 1), and the purified solution was concentrated under vacuum to give compound 6 (190 mg, 471.09 umol, 23.12% yield) as a yellow oil. LCMS: Rt=0.545 min, m / z=285.0 (M+H) +

[0364] Compound 7 (535.18 mg, 2.11 mmol, 1 eq.), KOAc (413.67 mg, 4.22 mmol, 2 eq.) and Pd(dppf)Cl2.CH2Cl2 (172.11 mg, 210.75 umol, 0.1 eq.) were added to a glass bottle (40 mL) containing a solution of compound 6 (850 mg, 2.11 mmol, 1 eq.) in dioxane (10 mL), and the mixture was stirred at 100 ° C. under N2 for 12 hours. The reaction mixture was filtered under vacuum to give a filtrate, which was then concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=10 / 1 to 5 / 1), and the purified solution was concentrated under vacuum to give compound 8 (600 mg, 1.33 mmol, 63.21% yield) as a yellow oil. LCMS: Rt=0.623min, m / z=333.1(M+H) +

[0365] To a round-necked flask (100 mL) containing a solution of compound 8 (600 mg, 1.33 mmol, 1 eq.) in AcOH (6 mL) was slowly added H2O2 (7.08 g, 62.44 mmol, 6 mL, 30% purity, 46.87 eq.) at 20°C. The mixture was then stirred at 20°C for 1 h. The reaction mixture was quenched with Na2SO3 (60 ml) and extracted with DCM (60 mL x 3), the combined organic phases were dried and concentrated at 20°C to give compound 9 (430 mg, 1.26 mmol, 94.82% yield) as a yellow oil, which was used directly in the next step. LCMS: Rt=0.492 min, m / z=223.2 (M+H) +

[0366] To a glass bottle (40 mL) containing a solution of methyl compound 9 (330 mg, 969.39 umol, 1 eq.) in acetone (4 mL), K2CO3 (267.95 mg, 1.94 mmol, 2 eq.), KI (16.09 mg, 96.94 umol, 0.1 eq.) and compound 10 (140.73 mg, 1.16 mmol, 1.2 eq.) were added, and the mixture was stirred at 60 ° C for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x3), the combined organic phases were dried and concentrated under vacuum to give compound 11 (360 mg, 946.16 umol, 97.60% yield) as a yellow oil, which was used directly in the next step. LCMS: Rt = 0.553 min, m / z = 263.1 (M + H) +

[0367] LAH (53.87 mg, 1.42 mmol, 1.5 eq.) was slowly added to a slenk tube (20 mL) containing a solution of methyl compound 11 (360 mg, 946.16 umol, 1 eq.) in 2-MeTHF (5 mL) at 0°C, and the mixture was stirred at 0°C for 1 hour. After the reaction was completed, Na2SO4·10H2O (200 mg) was added to the resulting mixture, and the mixture was then filtered and the filtrate was concentrated to give compound 12 (230 mg, 736.21 umol, 77.81% yield) as a white solid, which was used directly in the next step. LCMS: Rt=0.421 min, m / z=195.2 (M+H) +

[0368] K2CO3(203.50mg, 1.47mmol, 2 equivalents), KI(12.22mg, 73.62umol, 0.1 equivalents) and compound 13(89.06mg, 736.21umol, 1 equivalents) were added to a glass bottle (40mL) containing a solution of compound 12(230mg, 736.21umol, 1 equivalent) in acetone (3mL), and the mixture was then stirred at 60°C for 12 hours. The reaction mixture was poured into water (20mL) and extracted with EtOAc(20mL x3), the combined organic phases were dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=5 / 1), the purified solution was concentrated under vacuum to give compound 14(220mg, 624.16umol, 84.78% yield) as a colorless oil. LCMS: Rt=0.495min, m / z=235.2(M+H) +

[0369] To a solution of compound 14 (220 mg, 624.16 umol, 1 eq.) in DCM (3 mL) in a glass bottle (40 mL) was added MnO2 (1.09 g, 12.48 mmol, 20 eq.) and the mixture was stirred at 20 °C for 12 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated to give compound 15 (190 mg, 542.15 umol, 86.86% yield) as a colorless oil, which was used directly in the next step. LCMS: Rt = 0.540 min, m / z = 233.2 (M+H) +

[0370] AcOH (3.26 mg, 54.21 umol, 3.10 uL, 0.1 eq) and THF (2M, 813.22 uL, 3 eq) containing compound 15 (190 mg, 542.15 umol, 1 eq) were added to a 100 mL three-necked flask containing a solution of MeOH (2 mL) at 20 ° C, and the mixture was stirred at 20 ° C for 1 hour. Then, NaBH (41.02 mg, 1.08 mmol, 2 eq) was added to the mixture at 0 ° C, and the mixture was stirred at 20 ° C for 1 hour. The reaction mixture was quenched with saturated NaHCO aqueous solution (20 mL) and extracted with dichloromethane (20 mL x 3), and the combined organic phases were dried and concentrated under vacuum to give compound 16 (120 mg, 328.30 umol, 60.56% yield) as a colorless oil, which was used directly in the next step. LCMS: Rt=0.394min, m / z=366.3(M+H) +

[0371] EDCI (39.34 mg, 205.19 umol, 1.5 eq.), DMAP (1.67 mg, 13.68 umol, 0.1 eq.) and compound 16 (50 mg, 136.79 umol, 1 eq.) were added to a glass bottle (8 mL) containing a solution of compound 17 (37.24 mg, 136.79 umol, 1 eq.) in DCM (1 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative-TLC (SiO2, PE / EtOAc=1 / 1), and the purified solution was concentrated under vacuum to give compound 18 (60 mg, 96.81 umol, 70.77% yield) as a colorless oil. LCMS: Rt=0.598 min, m / z=502.3 (M+H) +

[0372] Pd(PPh3)4 (11.19 mg, 9.68 umol, 0.1 eq.) was added to a Schlenk tube (20 mL) containing a solution of compound 18 (60 mg, 96.81 umol, 1 eq.) in THF (1 mL), and then NaBH4 (36.63 mg, 968.10 umol, 10 eq.) was added to the mixture at 0 ° C. The mixture was stirred at 20 ° C. under N2 for 1 hour. The reaction mixture was poured into saturated NH4Cl (20 mL) and extracted with EtOAc (20 mL x 3), the combined organic phases were dried and concentrated under vacuum to give compound 19 (40 mg, 69.00 umol, 71.27% yield) as a brown oil, which was used directly in the next step. LCMS: Rt = 0.550 min, m / z = 462.3 (M + H) +

[0373] In the round-bottom flask (100mL) of the solution containing compound 19 (40mg, 69.00umol, 1 equivalent), TFA (1.54g, 13.51mmol, 1mL, 195.74 equivalent) and DCM (0.5mL) are added, and then the mixture is stirred at 20 ℃ for 1 hour.By reaction mixture saturated NaHCO the aqueous solution (10mL) is alkalized, then reaction mixture H o (10mL) is diluted and extracted with EA (10mL x3).By the organic layer salt water washing merged, through Na sO dry, filter and under reduced pressure concentrate, obtain residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 44%-74%, 9min), and the purified solution was lyophilized to obtain compound 061 (13.7 mg, 29.51umol, 42.76% yield, 96.8% purity) as a brown solid, LCMS: Rt=0.456min, m / z=450.2 (M+H) + 1H NMR (400MHz, chloroform-d) δ = 8.12-8.09 (m, 1H), 7.44 (d, J = 1.1Hz, 1H), 7.38-7.34 (m, 1H), 7.32 (d, J = 7.6Hz, 1H), 7.23 (br d,J=7.8Hz,1H),7.19(dd,J=2.3,10.2Hz,1H),7.09(d,J=7.3Hz,2H),7.03(dt,J=1.7,8.5Hz, 1H),4.89(s,2H),3.80-3.73(m,1H),3.05-3.01(m,3H),0.83-0.78(m,2H),0.77-0.72(m,2H).

[0374] Compound 063 was prepared in a manner similar to Scheme 15 and isolated as a yellow solid (26 mg, 58.60 umol, 55.45% yield, 98.6% purity). LCMS: Rt = 0.447 min, m / z = 438.2 (M+H) + 1H NMR (400 MHz, chloroform-d) δ = 8.04-8.01 (m, 1H), 7.31-7.26 (m, 2H), 7.25 (s, 1H), 7.24-7.21 (m, 2H), 7.01-6.99 (m, 1H), 6.99-6.97 (m, 2H), 6.97-6.93 (m, 1H), 4.81-4.79 (m, 2H), 4.02-3.96 (m, 2H), 2.94 (s, 3H), 1.31-1.27 (m, 3H).

[0375] Compound 148 was prepared in a manner similar to Scheme 15 and isolated as a white solid (9.7 mg, 21.51 umol, 12.21% yield, 97% purity). LCMS: Rt = 0.488 min, m / z = 438.1 (M+H + )1H NMR (400 MHz, CHLOROFORM-d) δ=8.03(s,1H),7.41-7.30(m,5H),7.09(s,3H),5.09(s,2H),4.08(q,J=7.0Hz,2H),3.10-3.08(m,3H),1.40-1.36(m,3H).

[0376] Compound 178 was prepared in a manner similar to Scheme 15 and isolated as a white solid (21.8 mg, 48.03 umol, 31.17% yield). H-NMR: (400 MHz, chloroform-d) δ = 8.00 (s, 1H), 7.41 (s, 1H), 7.36-7.33 (m, 2H), 7.32-7.28 (m, 1H), 7.11 (d, J = 1.3 Hz, 1H), 6.98 (s, 1H), 6.86-6.83 (m, 2H), 4.91 (s, 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 1.30 (t, J = 6.9 Hz, 3H). LCMS: Rt = 0.486 min, m / z = 454.0 (M+H + ).

[0377] Scheme 16

[0378]

[0379] Pd(dppf)Cl2·CH2Cl2 (117.89 mg, 144.36 umol, 0.1 eq.) and K2CO3 (399.03 mg, 2.89 mmol, 2 eq.) were added to a glass bottle (40 mL) containing a solution of compound 1 (400 mg, 1.44 mmol, 1 eq.) and compound 2 (455.92 mg, 2.89 mmol, 2 eq.) in dioxane (10 mL). The mixture was stirred at 100 ° C under N2 atmosphere for 12 hours. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over [Na2SO4], filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=0 / 1 to 5 / 1), and the purified solution was concentrated in vacuo to give compound 3 (340 mg, 1.10 mmol, 75.91% yield) as a white solid. LCMS: Rt=0.495 min, m / z=311.2 (M+H) +

[0380] To a round-bottom flask (100 mL) containing a solution of compound 3 (340 mg, 1.10 mmol, 1 eq.) in MeOH (5 mL) and H2O (1.7 mL) was added LiOH.H2O (137.95 mg, 3.29 mmol, 3 eq.). The mixture was stirred at 20 °C for 1 hour. THF (5 mL) and NaOH (131.49 mg, 3.29 mmol, 3 eq.) were added to the reaction mixture, which was stirred at 20 °C for another 1 hour. The organic solvent was evaporated under vacuum, the resulting mixture was acidified to pH 4 with 1N HCl, filtered, the filter cake was washed with water (20 mL), then dissolved in MeOH (20 mL), and concentrated in vacuo to give compound 4 (300 mg, 1.01 mmol, 92.41% yield) as a white solid without further purification, and used in the next step. LCMS: Rt=0.398min, m / z=295.0(MH) +

[0381] EDCI (291.20 mg, 1.52 mmol, 1.5 eq.) and DMAP (12.37 mg, 101.27 umol, 0.1 eq.) were added to a round-bottom flask (50 mL) containing a solution of compound 4 (300 mg, 1.01 mmol, 1 eq.) and compound 5 (354.93 mg, 1.01 mmol, 1 eq.) in DCM (10 mL). The mixture was stirred at 20 ° C for 12 hours. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 0 / 1), and the purified solution was concentrated in vacuo to give compound 6 (380 mg, 604.41 umol, 59.68% yield) as a green oil. LCMS: Rt=0.572 min, m / z=629.3 (M+H) +

[0382] To a round-bottom flask (50 mL) containing a solution of compound 6 (380 mg, 604.41 umol, 1 eq.) in MeOH (5 mL) was added LiBH4 in THF (2 M, 906.61 uL, 3 eq.) at 0 °C. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (30 mL x 3), and the combined organic phases were dried and concentrated under vacuum to give a residue. The residue was purified by preparative-TLC (SiO2, dichloromethane: methanol = 10: 1), and the purified solution was concentrated in vacuo to give compound 7 (210 mg, 349.59 umol, 57.84% yield) as a colorless oil. LCMS: Rt = 0.458 min, m / z = 601.8 (M+H) +

[0383] TFA (3.08 g, 27.01 mmol, 2 mL, 540.87 equiv) was added to a round-bottom flask (50 mL) containing a solution of compound 7 (30 mg, 49.94 umol, 1 equiv) in DCM (1 mL). The mixture was stirred at 20 ° C for 3 hours. The reaction mixture was concentrated at 20 ° C and under reduced pressure to obtain a residue. The residue was dissolved in dichloromethane (2 mL) and basified to pH of about 7 at 20 ° C with NaHCO (5 mg), then filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 9 min), and the purified solution was lyophilized to obtain 131 (8.5 mg, 18.07 umol, 36.18% yield, 100% purity) as a white solid. LCMS: Rt=0.363 min, m / z=471.3 (M+H) + 1H NMR (400 MHz, chloroform-d) δ = 8.35-8.28 (m, 2H), 6.95 (br d, J = 7.3 Hz, 2H), 6.90-6.80 (m, 3H), 5.21-5.16 (m, 2H), 4.98-4.91 (m, 2H), 4.11-4.01 (m, 2H), 3.10-3.03 (m, 3H), 1.37-1.30 (m, 3H).

[0384] Compound 084 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 084 (41.0 mg, 85.96 umol, 52.20% yield, 100% purity) was obtained as a white solid. LCMS: Rt=0.422 min, m / z=476.16 (M+H + ) 1 HNMR: (400MHz, chloroform-d) δ = 12.43-12.15 (m, 1H), 8.28 (d, J = 5.6Hz, 2H), 7.55 (s,1H),7.48-7.40(m,1H),7.39-7.29(m,3H),7.07(dd,J=1.4,7.8Hz,1H) ,6.90(d,J=1.1Hz,1H),5.15(s,2H),4.95(s,2H),4.67(quin,J=7.0Hz,1 H),3.05(s,3H),2.49-2.36(m,2H),2.20-2.06(m,2H),1.91-1.77(m,2H).

[0385] Compound 085 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 085 (11.3 mg, 24.84 umol, 20.04% yield and 95.5% purity) was obtained as a white solid. LCMS: Rt=0.384 min, m / z=454.13 (M+H + ) 1 H NMR: (400MHz, chloroform-d)δ=12.33(br s,1H),8.27(s,2H),7.68(d,J=7.9Hz,1H),7.53(d,J=3.6Hz,1H),7.46(s,1H),7.37(d,J=5.0Hz,1H ),7.15-7.05(m,2H),5.14(s,2H),4.95(s,2H),3.96-3.80(m,1H),3.06(s,3H),0.92-0.86(m,4H).

[0386] Compound 087 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 087 (10.7 mg, 22.04 umol, 38.77% yield, 100% purity) was obtained as a white solid. LCMS: Rt=0.389 min, m / z=486.3 (M+H + )1H NMR (400 MHz, CHLOROFORM-d) δ=8.49(s,1H),8.41-8.33(m,1H),7.69-7.64(m,2H),7.62-7.57(m,1H),7.56-7.50(m,1H),7.22-7.18(m,1H),6.91-6.84(m,1H),5.30(s,2H),5.05-4.98(m,2H),3.78-3.71(m,1H),3.42-3.33(m,2H),1.38-1.34(m,3H),0.84-0.78(m,2H),0.75-0.68(m,2H).

[0387] Compound 098 was prepared using LiOH instead of NaOH in a manner similar to Scheme 16. Compound 087 (15 mg, 34.29 umol, 29.95% yield) was obtained as a white solid. 1H NMR: (400MHz, DMSO-d6)δ=12.87-12.73(m,1H),9.15(br s,1H),8.02-7.76(m,1H),7.54-7.38(m,1H),7.28-6.84(m,7H),4.93-4.72(m,2H),3.82 -3.56(m,2H),3.09-2.97(m,3H),1.25-1.00(m,3H).LCMS:Rt=0.449min,m / z=438.1(M+H + ).

[0388] Compound 104 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 104 (14.28 mg, 29.91 umol, 30.29% yield, 100% purity) was obtained as a white solid. LCMS: Rt=0.368 min, m / z=478.1 (M+H + ).HNMR: (400MHz, CHLOROFORM-d)δ=12.46-11.85(m,1H),8.29(d,J=3.6Hz,2H),7.54(s,1H),7.46-7.34(m,2H),6.91-6.84(m,2H),5.15(s,2H),4.95(s,2H),4.07(q,J=6.8Hz,2H),3.05(s,3H),1.34(t,J=6.8Hz,3H).

[0389] Compound 106 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 106 (11.2 mg, 25.17 umol, 27.11% yield, 99% purity) was obtained as a white solid. LCMS: Rt=0.390 min, m / z=441.5 (M+H + )1H NMR (400MHz, chloroform-d) δ = 12.57-11.76 (m, 1H), 8.26 (d, J = 6.5Hz, 2H), 7.66 (br s,1H),7.46(d,J=5.1Hz,1H),7.14(t,J=4.4Hz,1H),6.92-6.85(m,2H),5.13( s, 2H), 4.92 (s, 2H), 4.17 (q, J = 6.9Hz, 2H), 3.04 (s, 3H), 1.51 (t, J = 6.9Hz, 3H).

[0390] Compound 107 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 107 (10.3 mg, 21.75 umol, 24.82% yield, 93% purity) was obtained as a white solid. LCMS: Rt=0.376 min, m / z=441.2 (M+H + )1H NMR (400MHz, chloroform-d)δ=12.49-11.88(m,1H),8.31-8.21(m,2H),7.66-7.62(m,1H),7.44-7.33(m,2H),6 .91-6.81(m,2H),5.13(s,2H),4.93(s,2H),4.08(q,J=6.9Hz,2H),3.05(s,3H),1.41(t,J=6.9Hz,3H).

[0391] Compound 109 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 109 (18 mg, 40.09 umol, 21.83% yield and 99% purity) was obtained as a white solid. LCMS: Rt=0.748 min, m / z=445.3 (M+H + ) 1 HNMR: (400 MHz, chloroform-d) δ = 12.18 (s, 1H), 9.13 (s, 1H), 8.51-8.21 (m, 2H), 7.54-7.33 (m, 3H), 7.27-7.17 (m, 2H), 7.15-6.98 (m, 2H), 6.18 (s, 1H), 3.78 (s, 1H), 2.82 (s, 3H), 2.46-2.22 (m, 2H), 1.29-1.16 (m, 3H), 0.88-0.72 (m, 4H).

[0392] Compound 111 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 111 (6.5 mg, 14.24 umol, 20.89% yield, 100% purity) was obtained as a white solid. LCMS: Rt=0.420 min, m / z=457.2 (M+H +).HNMR: (400MHz, chloroform-d)δ=11.94-11.43(m,1H),7.98(s,1H),7.64(br d,J=5.9Hz,2H),7.60-7.48(m,1H),7.48-7.48(m,1H),7.24(s,1H),7.13(s,1H),7.01(s,1H),6.88(br d,J=8.9Hz,1H),4.92(s,2H),3.72(br d,J=2.4Hz,1H),3.04(s,3H),0.82-0.72(m,2H),0.67(br s,2H).

[0393] Compound 112 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 112 (10.2 mg, 23.83 umol, 29.11% yield, 98% purity) was obtained as a white solid. LCMS: Rt=0.451 min, m / z=420.0 (M+H + )1H NMR (400 MHz, CHLOROFORM-d) δ=8.01(s,1H),7.44-7.34(m,5H),7.14-7.09(m,1H),7.01-6.97(m,1H),6.89-6.82(m,2H),4.91(s,2H),4.08-3.97(m,2H),3.04(s,3H),1.32-1.29(m,3H).

[0394] Compound 113 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 113 (5.3 mg, 11.38 umol, 13.56% yield, 100% purity) was obtained as a white solid. LCMS: Rt=0.499 min, m / z=466.2 (M+H + )1H NMR (400 MHz, CHLOROFORM-d)δ=7.99(s,1H),7.33(s,3H),7.23(s,2H),7.12(s,1H),6.98(s,1H),6.87(d,J=8.8Hz,1H),4.92(s,2H),3.73(s,1H),3.04(s,3H),0.78(d,J=4.9Hz,2H),0.70(s,2H).

[0395] Compound 114 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH and isolated as a yellow solid (16.5 mg, 38.24 umol, 10.74% yield, 100% purity). LCMS: Rt = 0.451 min, m / z = 431.16 (M+H + )1 H NMR: (400MHz, DMSO-d6) δ = 12.78 (br d, J = 17.1Hz, 1H), 9.16 (br s, 1H), 7.89 (br s, 1H), 7.40 (br dd, J = 1.1, 5.6Hz, 1H), 7.33 (br s,3H),7.26-7.19(m,1H),7.12-6.98(m,1H),6.97-6.85(m,2H),4.99-4.74( m,2H),3.12-2.99(m,3H),2.05(s,1H),0.85-0.55(m,2H),0.50-0.26(m,2H).

[0396] Compound 131 was prepared in a manner similar to Scheme 16 and isolated as a white solid (8.5 mg, 18.07 umol, 36.18% yield, 100% purity). LCMS: Rt = 0.363 min, m / z = 471.3 (M+H) + 1H NMR (400 MHz, chloroform-d) δ = 8.35-8.28 (m, 2H), 6.95 (br d, J = 7.3 Hz, 2H), 6.90-6.80 (m, 3H), 5.21-5.16 (m, 2H), 4.98-4.91 (m, 2H), 4.11-4.01 (m, 2H), 3.10-3.03 (m, 3H), 1.37-1.30 (m, 3H).

[0397] Compound 151 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 151 (12.82 mg, 27.72 umol, 18.26% yield, 100% purity) was obtained as a white solid. LCMS: Rt=0.322 min, m / z=463.1 (M+H + ) 1 H NMR: (400MHz, DMSO-d6) δppm 13.38-13.67(m,1H)8.43-8.64(m,1H)8.11-8.25(m,1H)7.38-7.52(m,4H)7.13-7.24(m,2H)6.71-6. 85(m,1H)5.61-5.82(m,1H)5.49(s,1H)4.90-5.00(m,4H)4.64-4.88(m,2H)4.29-4.55(m,2H)2.98(br d,J=2.00Hz,3H).

[0398] Compound 155 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 155 (12.7 mg, 19.83 umol, 22.65% yield, 98.2% purity) was obtained as a white solid. LCMS: Rt=0.326 min, m / z=481.1 (M+H) + 1H NMR (400MHz, chloroform-d) δ = 8.37 (s, 1H), 8.33 (s, 1H), 7.39 (d, J = 7.8Hz, 1H), 7.13 (dd, J = 1.3, 7.8Hz, 1H) ,7.09(dd,J=2.1,8.3Hz,2H),6.87-6.80(m,1H),6.61(d,J=1.0Hz,1H),5.28-5.23(m,1H),5.22(br s,2H),5.00-4.97(m,2H),4.96-4.94(m,2H),4.72(dd,J=5.2,7.4Hz,2H),3.05(s,3H).

[0399] Compound 161 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 161 (23.8 mg, 46.13 umol, 52.64% yield and 96.4% purity) was obtained as a white solid. LCMS: Rt=0.419 min, m / z=497.1 (M+H + ) 1 HNMR: (400MHz, chloroform-d) δ = 12.34-11.99 (m, 1H), 8.28 (s, 2H), 7.35 (d, J = 5.3Hz, 2H), 7.31 (d, J = 1.3Hz, 1H), 7.20 (d, J = 0.9Hz, 1H), 7.17 ( d,J=1.3Hz,1H),7.12-7.07(m,1H),5.15(s,2H),4.96(s,2H),3.76-3.65(m,1H),3.08(s,3H),0.79-0.74(m,2H),0.68-0.62(m,2H).

[0400] Compound 162 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 162 (37 mg, 76.94 umol, 39.18% yield and 100% purity) was obtained as a white solid. LCMS: Rt=0.404 min, m / z=481.1 (M+H + ) 1 HNMR: 1H NMR (400 MHz, chloroform-d) δ = 12.17 (s, 1H), 8.28 (s, 2H), 7.42-7.34 (m, 1H), 7.31 (d, J = 1.1 Hz, 1H), 7.17 (d, J = 1.0 Hz, 1H), 7.11-7.03 (m, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 9.4 Hz, 1H), 5.14 (s, 2H), 4.95 (s, 2H), 3.75-3.67 (m, 1H), 3.08 (s, 3H), 0.82-0.72 (m, 2H), 0.69-0.60 (m, 2H).

[0401] Compound 165 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 165 (7 mg, 14.07 umol, 12.60% yield, 99.8% purity) was obtained as a white solid. LCMS: Rt=0.481 min, m / z=486.2 (M+H + ) 1 H NMR: (400 MHz, CHLOROFORM-d) δ=8.31(s,1H),8.28(s,1H),7.18(s,1H),6.88(brd,J=7.2Hz,2H),6.87-6.79(m,2H),5.16(s,2H),4.99(s,2H),3.74(tt,J=2.8,6.0Hz,1H),3.34(q,J=7.2Hz,2H),1.33(t,J=7.2Hz,3H),0.84-0.76(m,2H),0.76-0.70(m,2H).

[0402] Compound 175 was prepared in a manner similar to Scheme 16 using LiOH instead of NaOH. Compound 175 (9.2 mg, 19.52 umol, 23.39% yield, 99.5% purity) was obtained as a white solid. LCMS: Rt=0.366 min, m / z=468.14 (M+H) + 1H NMR (400 MHz, CHLOROFORM-d) δ = 12.59-12.17 (m, 1H), 8.38-8.31 (m, 2H), 7.43-7.36 (m, 1H), 7.16-7.13 (m, 1H), 7.11-7.07 (m, 1H), 7.07-7.03 (m, 1H), 7.02-6.97 (m, 1H), 6.93 (s, 1H), 5.21 (s, 2H), 4.96 (s, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.09 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H).

[0403] Solution 17

[0404]

[0405] To a solution of compound 1 (500 mg, 1.56 mmol, 1 eq.) and compound 2 (512.27 mg, 3.12 mmol, 281.47 uL, 2 eq.) in dioxane (5 mL) and H2O (0.5 mL) was added K2CO3 (431.64 mg, 3.12 mmol, 2 eq.) and Pd(dppf)Cl2.CH2Cl2 (127.52 mg, 156.16 umol, 0.1 eq.). The mixture was stirred at 100 °C under N2 atmosphere for 12 hours. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3), the combined organic phases were dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 10 / 1), and the purified solution was concentrated in vacuo to give compound 3 (200 mg, 721.14 umol, 46.18% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ=8.51 (d, J=8.3 Hz, 1H), 7.98 (d, J=3.3 Hz, 1H), 7.76 (dd, J=1.5, 8.3 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.49-7.45 (m, 1H), 4.45-4.39 (m, 2H), 4.39-4.34 (m, 2H), 1.65 (t, J=7.0 Hz, 3H), 1.45-1.41 (m, 3H)

[0406] To a solution of compound 3 (200 mg, 721.14 umol, 1 eq.) in EtOH (3 mL), H2O (1 mL) and THF (3 mL) was added LiOH · H2O (90.79 mg, 2.16 mmol, 3 eq.). The mixture was stirred at 20 ° C for 12 hours. The solvent was removed by evaporation under reduced pressure, and the mixture was then acidified to pH 4 with 1N HCl, and the suspension was then filtered to give compound 4 (130 mg, 521.49 umol, 72.31% yield) as a white solid, which was used in the next step. LCMS: Rt = 0.355 min, m / z = 247.9 (MH + )

[0407] EDCI (149.96 mg, 782.24 umol, 1 eq.) and DMAP (6.37 mg, 52.15 umol, 0.1 eq.) were added to a solution of compound 4 (130 mg, 521.49 umol, 1 eq.) and compound 5 (182.78 mg, 521.49 umol, 1 eq.) in DCM (3 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=3 / 1 to 0 / 1), and the purified solution was concentrated in vacuo to give compound 6 (180 mg, 309.41 umol, 59.33% yield) as a yellow oil. LCMS: Rt=0.561 min, m / z=582.2 (M+H + )

[0408] LiBH4 (2M, 773.52uL, 5 eq.) was added to a solution of compound 6 (180 mg, 309.41umol, 1 eq.) in MeOH (3 mL) at 0 °C. The mixture was stirred at 30 °C for 12 hours. The reaction mixture was poured into a saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (10 mL x 3), the combined organic phases were dried over anhydrous Na2SO4, and concentrated to give a residue. The residue was purified by preparative-TLC (SiO2, PE / EtOAc=0:1). The purified solution was concentrated in vacuo to give compound 7 (95 mg, 171.56umol, 55.45% yield) as a yellow oil. LCMS: Rt=0.400min, m / z=554.2 (M+H + )

[0409] MnO2 (298.29 mg, 3.43 mmol, 20 equivalents) was added to a solution of compound 7 (95 mg, 171.56 umol, 1 equivalent) in DCM (3 mL). The mixture was stirred at 30 ° C for 12 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by preparative-TLC (SiO2, PE / EtOAc=1:1). The purified solution was concentrated in vacuo to give compound 8 (45 mg, 81.56 umol, 47.54% yield) as a yellow oil.

[0410] MeMgBr (3M, 81.56uL, 3 eq.) was added to a Schlenk tube (40 mL) containing a solution of compound 8 (45 mg, 81.56umol, 1 eq.) in THF (2 mL) at -70 °C. The mixture was stirred at -70 °C for 1 hour. The reaction mixture was poured into saturated NH4Cl (5 mL). The solvent was extracted with EtOAc (5 mL x 3), the combined organic phases were dried and concentrated under vacuum to give (30 mg, 52.84umol, 64.78% yield) as a yellow solid, which was used in the next step. LCMS: Rt = 0.401 min, m / z = 568.4 (M + H + )

[0411] CsF (80.26 mg, 528.38 umol, 19.48 uL, 10 equiv.) was added to a solution of compound 9 (30 mg, 52.84 umol, 1 equiv.) in DMF (1 mL). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was filtered to give a residue. The residue was purified by preparative-HPLC (column: Phenomenex C18 150*25 mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 14 min). The purified solution was lyophilized to give 149 (5 mg, 11.43 umol, 21.63% yield, 100% purity) as a white solid. LCMS: Rt=0.571 min, m / z=438.0 (M+H + )1HNMR (400MHz, chloroform-d)δ=12.41-12.31(m,1H),8.48(d,J=8.5Hz,1H),8.33(s,1H),8.26(s,1H),7.95(d,J=3.1Hz,1H),7.46(d,J=3.3Hz,1H),7.1 8-7.13(m,2H),5.39-5.29(m,1H),4.95(s,2H),4.80-4.68(m,1H),4.31 (q,J=6.9Hz,2H),3.08-3.01(m,3H),1.70(d,J=6.6Hz,3H),1.61(s,3H).

[0412] Compound 067 was prepared in a manner similar to Scheme 17 and obtained as a brown solid (32.3 mg, 66.83 umol, 39.62% yield and 95.7% purity). LCMS: Rt=0.700 min, m / z=463.2 (M+H + ) 1H-NMR: (400MHz, chloroform-d)δ=12.31(br s,1H),8.32(s,1H),8.25(s,1H),7.42-7.35(m,2H),7.34-7.29(m,2H),7.09-7 .01(m,3H),5.33(d,J=6.6Hz,1H),4.99(s,2H),4.07(q,J=6.9Hz,2H),3.34(br d, J=7.0Hz, 2H), 1.70 (d, J=6.6Hz, 3H), 1.39 (t, J=6.9Hz, 3H), 1.31 (t, J=7.1Hz, 3H).

[0413] Compound 076 was prepared in a manner similar to Scheme 17 and obtained as a white solid (12.09 mg, 24.60 umol, 25.49% yield, 100% purity). LCMS: Rt=0.345 min, m / z=492.18 (M+H + ). 1 H NMR: (400MHz, chloroform-d)δ=12.16(br s,1H),8.46-8.16(m,2H),7.54(d,J=1.3Hz,1H),7.45-7.33(m,2H),6.94-6.84(m,2H),5.32(q,J=6.6 Hz, 1H), 4.94 (s, 2H), 4.07 (q, J = 6.9Hz, 2H), 3.05 (s, 3H), 1.68 (d, J = 6.6Hz, 3H), 1.33 (t, J = 7.0Hz, 3H).

[0414] Compound 080 was prepared in a manner similar to Scheme 17 and obtained as a white solid. LCMS: Rt=0.369min, m / z=468.1(M+H+).HNMR: (400MHz, chloroform-d)δ=12.49-12.28(m ,1H),8.37-8.23(m,2H),7.77(s,1H),7.70(d,J=7.8Hz,1H),7.63(d,J=7.9Hz,1 H),7.52(d,J=7.8Hz,1H),7.50-7.46(m,1H),7.32(d,J=7.8Hz,1H),7.16-7.12( m,1H),5.46-5.30(m,1H),4.97(s,2H),3.83-3.74(m,1H),3.09(s,3H),1.71(br d,J=6.1Hz,3H),0.86-0.81(m,2H),0.77-0.73(m,2H).

[0415] Compound 081 was prepared in a manner similar to Scheme 17 and obtained as a white solid (2.6 mg, 5.49 umol, 16.53% yield, 99.7% purity). LCMS: Rt=0.370 min, m / z=473.0 (M+H + )1H NMR (400 MHz, CHLOROFORM-d) δ=12.47-12.15 (m, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.47-7.43 (m, 1H), 6.88 (s, 2H), 6.82 (s, 1H), 5.42-5.32 (m, 1H), 4.96-4.90 (m, 2H), 4.20 (q, J=7.0 Hz, 2H), 3.05 (s, 3H), 1.71-1.70 (m, 3H), 1.55-1.53 ​​(m, 3H).

[0416] Compound 083 was prepared in a manner similar to Scheme 17 and obtained as a yellow solid (7.1 mg, 15.83 umol, 9.16% yield and 100% purity). LCMS: Rt=0.380 min, m / z=448.16 (M+H + ) 1 H NMR: (400MHz, chloroform-d) δ = 12.50-12.18 (m, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.68 (d, J = 7.9Hz, 1H), 7.53 (d, J = 2.8Hz, 1H), 7.47 (d, J = 1.1Hz, 1H), 7 .37(d,J=4.5Hz,1H),7.14-7.02(m,2H),5.30(q,J=6.5Hz,1H),4.94(s ,2H),3.95-3.85(m,1H),3.06(s,3H),1.67(s,3H),0.93-0.85(m,4H).

[0417] Compound 088 was prepared in a manner similar to Scheme 17 and obtained as a yellow solid (4.6 mg, 10.12 umol, 9.86% yield, 100% purity). LCMS: Rt=0.388 min, m / z=455.2 (M+H +)1H NMR (400 MHz, CHLOROFORM-d) δ=8.40(s,1H),8.30(s,1H),7.64(s,1H),7.43-7.40(m,1H),7.38-7.34(m,1H),6.90-6.85(m,2H),5.45-5.35(m,1H),4.95(s,2H),4.09(q,J=7.0Hz,2H),3.08(s,3H),1.73(d,J=6.6Hz,3H),1.43-1.40(m,3H).

[0418] Compound 089 was prepared in a manner similar to Scheme 17 and obtained as a yellow solid (6.3 mg, 13.26 umol, 19.88% yield, 98.8% purity). LCMS: Rt=0.348 min, m / z=470.3 (M+H + )1H NMR (400MHz, chloroform-d)δ=8.43(s,1H),8.30(s,1H),7.88-7.83(m,1H),7.79-7.74(m,1H),7.64(d,J=7.8Hz,1H),7.55-7.50(m,1H),7.36-7.32(m,1H),7.09-7.05(m,1H),7.01 (s,1H),5.47-5.41(m,1H),5.00(d,J=4.5Hz,2H),4.07(q,J=6.8Hz,2H),3.39-3.28(m ,2H),2.28-2.18(m,1H),1.75(d,J=6.6Hz,3H),1.40-1.35(m,3H),1.34-1.30(m,3H).

[0419] Compound 090 was prepared in a manner similar to Scheme 17 and obtained as a yellow solid (2.6 mg, 5.38 umol, 8.12% yield and 98% purity). LCMS: Rt=0.352 min, m / z=474.2 (M+H + ).1H NMR: (chloroform-d): δ12.07-12.26(1H,m),8.23-8.33(2H,m),7.61-7.76(3H,m),7.51-7.57(1H,m),6.84-6.91(2H,m),5. 31(1H,q,J=6.5Hz), 4.94(2H,s), 4.06(2H,q,J=7.0Hz), 3.06(3H,s), 1.68(3H,d,J=6.6Hz), 1.32(3H,t,J=6.9Hz).

[0420] Compound 091 was prepared in a manner similar to Scheme 17 and obtained as a yellow solid (9.6 mg, 19.58 umol, 24.11% yield and 99% purity). LCMS: Rt=0.380 min, m / z=486.3 (M+H + ).1H NMR: (Chloroform-d): δ12.27(1H,s),8.36(1H,s),8.29(1H,s),7.63-7.69(2H,m),7.57-7.61(1H,m),7.50-7.56 (1H,m),7.25-7.26(1H,m),6.88-6.95(1H,m),5.37(1H,q,J=6.5Hz),4.96(2H,s),3.77(1H,td,J=2.9and 5.9Hz), 3.10 (3H, s), 1.71 (3H, d, J = 6.6Hz), 0.78-0.86 (2H, m), 0.68-0.75 (2H, m).

[0421] Compound 101 was prepared in a manner similar to Scheme 17 and obtained as a white solid (24.6 mg, 50.85 umol, 68.62% yield, 98.594% purity). LCMS: Rt = 0.370 min, m / z = 477.4 (M+H + )1H NMR: (400MHz, chloroform-d) δppm8.41 (s, 1H) 8.33 (s, 1H) 7.45 (d, J = 1.13Hz, 2H) 7.30-7.36 (m, 4H) 7.11 (dd, J = 7.75, 1.38Hz, 1H) 5.42 (q, J = 6. 55Hz,1H)4.98(d,J=1.25Hz,2H)3.75-3.80(m,1H)3.09(s,3H)2.63(s,1H)1.72(d,J=6.75Hz,3H)0.79-0.85(m,2H)0.73-0.78(m,2H).

[0422] Compound 102 was prepared in a manner similar to Scheme 17 and obtained as a white solid (22 mg, 44.00 umol, 39.30% yield, 99% purity). LCMS: Rt = 0.424 min, m / z = 459.2 (M+H + ). 1H NMR: (chloroform-d): δppm 0.75-0.79(m,2H)0.81-0.85(m,2H)1.69(d,J=6.63Hz,3H)3.07(s,3H)3.78(tt,J=5.88,2.94Hz,1H)4.52-4.83(m,1H)4.96(s,2H) 5.32(q,J=6.09Hz,1H)7.05-7.13(m,3H)7.24(s,1H)7.32(d,J=7.75Hz,1H)7.45(d,J=1.38Hz,1H)8.26(s,1H)8.31(s,1H)12.30(br s,1H).

[0423] Compound 115 was prepared in a manner similar to Scheme 17 and obtained as a white solid (4.6 mg, 9.29 umol, 38.74% yield, 100% purity). LCMS: Rt = 0.418 min, m / z = 495.4 (M+H + )1H NMR (400 MHz, CHLOROFORM-d) δ=12.46-12.00 (m, 1H), 8.33-8.21 (m, 2H), 7.38-7.31 (m, 3H), 7.25-7.20 (m, 2H), 6.91-6.86 (m, 1H), 5.32 (q, J=6.5 Hz, 1H), 4.95 (s, 2H), 3.75 (td, J=3.0, 5.7 Hz, 1H), 3.08 (s, 3H), 1.69 (d, J=6.5 Hz, 3H), 0.83-0.76 (m, 2H), 0.75-0.69 (m, 2H).

[0424] Compound 118 was prepared in a manner similar to Scheme 17 and obtained as a white solid (8.3 mg, 17.74 umol, 35.29% yield, 99.7% purity). LCMS: Rt = 0.384 min, m / z = 466.9 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 8.43-8.41 (m, 1H), 8.35-8.31 (m, 1H), 7.43-7.36 (m, 1H), 7.21-7.12 (m, 2H), 7.11-7.05 (m, 1H), 6.90-6.84 (m, 2H), 5.44 (q, J = 6.6 Hz, 1H), 4.96 (s, 2H), 4.08-4.01 (m, 2H), 3.09 (s, 3H), 1.76-1.72 (m, 3H), 1.35-1.30 (m, 3H).

[0425] Compound 152 was prepared in a manner similar to Scheme 17 and obtained as a white solid (11.83 mg, 23.81 umol, 49.77% yield, 100% purity). LCMS: Rt = 0.379 min, m / z = 497.3 (M+H + )1H NMR: (400MHz, chloroform-d)δ=12.72-12.19(m,1H),8.41-8.39(m,1H),8.34(s,1H),7.39(d,J=7.9Hz,1H),7.33(s,1H),7.22-7.17(m, 1H),7.15-7.10(m,2H),6.62-6.60(m,1H),5.28-5.24(m,1H),5.23(s,2H),4.99-4.95(m,4H),4.74-4.69(m,2H),3.06(s,3H).

[0426] Compound 156 was prepared in a manner similar to Scheme 17 using TFA instead of CsF and obtained as a colorless solid (18.7 mg, 38.26 umol, 52.13% yield, 98.8% purity). LCMS: Rt=0.363 min, m / z=483.2 (M+H) + 1H NMR (400MHz, chloroform-d) δ = 8.38 (s, 1H), 8.32 (s, 1H), 7.43-7.36 (m, 1H), 7.15 (d ,J=1.3Hz,1H),7.11-7.06(m,1H),7.04(d,J=7.6Hz,1H),6.99(td,J=1.8,9 .7Hz,1H),6.94(d,J=1.1Hz,1H),5.39(q,J=6.4Hz,1H),4.95(s,2H),3.99( q, J=7.0Hz, 2H), 3.08 (s, 3H), 1.70 (d, J=6.6Hz, 3H), 1.24 (t, J=7.0Hz, 3H).

[0427] Compound 157 was prepared in a manner similar to Scheme 17 and obtained as a white solid (10.2 mg, 21.29 umol, 25.05% yield and 95.6% purity). LCMS: Rt = 0.356 min, m / z = 457.1 (M+H + ) 1 H NMR: 1H NMR (400 MHz, CHLOROFORM-d) δ = 12.36 (d, J = 4.1 Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.39-8.20 (m, 2H), 7.19 (s, 1H), 7.16-7.09 (m, 2H), 5.17 (s, 2H), 4.96 (s, 2H), 4.30 (q, J = 6.9 Hz, 2H), 3.03 (s, 3H), 1.62 (s, 3H).

[0428] Compound 158 was prepared in a manner similar to Scheme 17 and obtained as a white solid (1.9 mg, 3.73 umol, 4.49% yield, 92.7% purity). LCMS: Rt = 0.372 min, m / z = 471.11 (M+H + ) 1 H NMR: (400 MHz, CHLOROFORM-d) δ = 12.41-12.04 (m, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.19 (s, 1H), 7.16-7.09 (m, 2H), 5.30 (q, J = 6.7 Hz, 1H), 4.93 (s, 2H), 4.30 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 1.67 (d, J = 6.6 Hz, 3H), 1.62 (s, 3H).

[0429] Compound 163 was prepared in a manner similar to Scheme 17 and obtained as a white solid (5.3 mg, 11.21 umol, 26.96% yield, 99.6% purity). LCMS: Rt = 0.411 min, m / z = 471.2 (M+H + )1H NMR (400MHz, chloroform-d) δ = 12.45-12.15 (m, 1H), 8.31-8.20 (m, 2H), 7.64 (d, J = 7.9Hz, 1H), 7.35-7.32 (m, 1H), 7.09-7.04 (m, 2H), 6.9 4-6.90(m,1H),5.35-5.26(m,1H),4.92(s,2H),4.20(q,J=6.9Hz,2H),3.07-2.99(m,3H),1.71-1.64(m,3H),1.59-1.54(m,3H).

[0430] Compound 164 was prepared in a manner similar to Scheme 17 and obtained as a white solid (3.4 mg, 7.35 umol, 8.63% yield, 98.8% purity). LCMS: Rt = 0.409 min, m / z = 457.2 (M+H +)1H NMR(400MHz, chloroform-d)δ=12.36-12.19(m,1H),8.32-8.21(m,2H),7.67-7.61(m, 1H),7.34(d,J=4.0Hz,1H),7.10-7.02(m,2H),6.92(d,J=4.1Hz,1H),5.14(br s,2H),4.97-4.89(m,2H),4.25-4.15(m,2H),3.03(s,3H),1.56(t,J=6.9Hz,3H).

[0431] Compound 166 was prepared in a manner similar to Scheme 17 and obtained as a white solid (7.8 mg, 15.42 umol, 38.83% yield, 98.7% purity). LCMS: Rt = 0.384 min, m / z = 499.1 (M+H) + 1H NMR (400MHz, chloroform-d) δ = 12.30-12.00 (m, 1H), 8.24 (s, 1H), 8.18 (br s,1H),7.32-7.25(m,2H),7.21-7.20(m,1H),7.11-7.03(m,2H),6.86(s,1H),5.25(br d,J=5.0Hz,1H),4.86(br s, 2H), 3.92 (q, J = 7.0Hz, 2H), 2.99 (s, 3H), 1.61 (br d, J = 6.5Hz, 3H), 1.17 (t, J = 6.9Hz, 3H).

[0432] Compound 168 was prepared in a manner similar to Scheme 17 and obtained as a white solid (8.5 mg, 17.44 umol, 35.65% yield, 99.1% purity). LCMS: Rt = 0.397 min, m / z = 483.2 (M+H) + 1H NMR (400MHz, chloroform-d) δppm 12.14-12.46(m,1H)8.18-8.33(m,2H)7.58-7.64(m,1H)7.42-7.48(m,1H)7.28-7.31(m,1H)7.06-7.12( m,1H)6.88-6.92(m,1H)5.24-5.35(m,1H)4.90-4.99(m,2H)3.84-3.94(m,1H)3.02-3.09(m,3H)1.67(br d,J=6.38Hz,3H)0.86-0.94(m,4H).

[0433] Compound 172 was prepared in a manner similar to Scheme 17 and obtained as a white solid (4.5 mg, 8.48 umol, 21.29% yield, 93.7% purity). LCMS: Rt = 0.410 min, m / z = 497.1 (M+H + )1H NMR (400 MHz, CHLOROFORM-d)δ=8.35(s,1H),8.28-8.25(m,1H),7.42(s,1H),7.37-7.34(m,2H),7.32-7.28(m,1H),6.84-6.80(m,1H),6.78(s,1H),5.39-5.33(m,1H),5.01-4.92(m,2H),4.07-3.99(m,2H),3.37-3.29(m,2H),1.71(d,J=6.6Hz,3H),1.34-1.29(m,6H).

[0434] Compound 176 was prepared in a manner similar to Scheme 17 and obtained as a white solid (6 mg, 12.53 umol, 9.54% yield). H-NMR: (400MHz, chloroform-d) δ = 8.30 (s, 1H), 8.23 ​​(s, 1H), 7.55 (d, J = 1.5Hz, 1H), 7.4 2(td,J=1.8,6.7Hz,1H),7.35-7.32(m,3H),7.04(dd,J=1.4,7.8Hz,1H),7.00( s,1H),5.31(q,J=6.5Hz,1H),4.97(s,2H),4.05(q,J=6.9Hz,2H),3.31(q,J=7 .1Hz, 2H), 1.68 (d, J = 6.6Hz, 3H), 1.37 (t, J = 7.0Hz, 3H), 1.29 (t, J = 7.1Hz, 3H).

[0435] Scheme 18

[0436]

[0437] Compound 2 (325.61 mg, 1.50 mmol, 1.2 equivalents) and K2CO3 (345.22 mg, 2.50 mmol, 2 equivalents) were added to an 8 mL glass bottle containing a solution of compound 1 (500 mg, 1.25 mmol, 1 equivalent) in DMF (5 mL), and the mixture was stirred at 20 ° C for 12 h. After the reaction was complete, the mixture was poured into water (20 mL), extracted with EtOAc (20 mL × 3), and the combined organic phases were washed with brine (20 ml × 3), dried over anhydrous Na2SO4, and concentrated to give a crude product. The crude product was purified by column chromatography (SiO2, PE: EtOAc = 2: 1 to 1: 1, desired product Rf = 0.4). Compound 3 (550 mg, 1.02 mmol, 82.05% yield) was obtained as a yellow oil. LCMS: Rt=0.554min, m / z=537.6(M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 8.67 (s, 1H), 8.43-8.40 (m, 1H), 5.92 (s, 2H), 5.44 (s, 2H), 4.11-4.09 (m, 3H), 3.56-3.49 (m, 2H), 1.46 (s, 18H), 0.93-0.87 (m, 2H), -0.05 (s, 9H).

[0438] To a 100 mL three-necked flask containing a solution of compound 3 (500 mg, 931.63 umol, 1 eq.) in MeOH (5 mL) was added THF (2 M, 2.33 mL, 5 eq.) containing LiBH4 at 0 ° C. The mixture was stirred at 20 ° C. for 2 h. After the reaction was completed, the reaction mixture was quenched with saturated NH4Cl aqueous solution (50 mL) at room temperature. The mixture was extracted with EtOAc (50 mL×3), the combined organic phases were dried over Na2SO4, and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (SiO2, PE:EtOAc=5:1 to 1:1, desired product Rf=0.4). Compound 4 (200 mg, 393.17 umol, 42.20% yield) was obtained as a white solid. LCMS: Rt=0.441 min, m / z=509.5 (M+H + )

[0439] To an 8 mL glass bottle containing a solution of compound 4 (50 mg, 98.29 umol, 1 eq.) in THF (1 mL), a solution of HCl in H2O (1.02 g, 27.98 mmol, 1 mL, 284.61 eq.) was added, and the mixture was stirred at 20 °C for 48 h. The reaction mixture was adjusted to pH = 7 with Na2CO3 at 20 °C. The mixture was extracted with EtOAc (5 mL x 3), and the combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4 and concentrated to give a crude product. The compound was used in the next step without further purification. Compound 5 (30 mg, 97.26 umol, 98.95% yield) was obtained as a colorless oil. LCMS: Rt = 0.235 min, m / z = 309.1 (M+Na + )

[0440] To a 100 mL round-bottom flask containing a solution of compound 5 (30 mg, 97.26 umol, 1 eq.) and compound 6 (25.31 mg, 97.26 umol, 1 eq.) in DCM (1 mL), EDCI (27.97 mg, 145.89 umol, 1.5 eq.) and DMAP (1.19 mg, 9.73 umol, 0.1 eq.) were added, and the mixture was stirred at 20 ° C for 12 h. After the reaction was complete, the mixture was concentrated to give a crude product. The crude product was purified by preparative-TLC (PE: EtOAc = 0: 1). Compound 7 (16 mg, 29.05 umol, 29.87% yield) was obtained as a colorless oil. LCMS: Rt = 0.450 min, m / z = 551.1 (M + H + )

[0441] To a 50 ml round-bottom flask containing a solution of compound 7 (16 mg, 29.05 umol, 1 eq.) in DCM (0.5 mL), TFA (770.00 mg, 6.75 mmol, 0.5 mL, 232.43 eq.) was added, and the mixture was stirred at 20 ° C for 2 h. The mixture was concentrated to give a crude product, which was dissolved in ACN (5 mL), and 1 g of Na2CO3 was added to the mixture, the mixture was stirred at 20 ° C for 0.5 h, and then the mixture was filtered and the filtrate was concentrated to give a crude product. The crude product was purified by preparative-HPLC (FA, column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 10 min), and the purified solution was lyophilized to give a white solid. Compound 150 (4.9 mg, 11.62 umol, 39.99% yield, 99.7% purity) was obtained as a white solid. LCMS: Rt=0.329 min, m / z=421.1 (M+H + ). 1 HNMR: (400MHz, chloroform-d)δ=8.24-8.21(m,2H),7.55(s,1H),7.41-7.28(m,5H),7.08-6.92(m,2H),5.10(s,2H),4.93(br d, J=6.0Hz, 2H), 4.15 (q, J=6.9Hz, 2H), 1.40 (br t, J=6.8Hz, 3H).

[0442] Solution 19

[0443]

[0444] To a solution of compound 1 (2 g, 7.32 mmol, 1 eq.) in EtOH (20 mL) and H2O (20 mL) was added LiOH·H2O (921.86 mg, 21.97 mmol, 3 eq.) in a 250 mL one-necked round-bottom flask, and the mixture was stirred at 25°C for 1 h. The solvent was removed by evaporation under reduced pressure, and the mixture was then acidified to pH = 4 with 1N HCl. The mixture was filtered and the filter cake was washed with 20 mL of MeOH and dried in vacuo to give compound 2 (1.7 g, 6.94 mmol, 94.73% yield) obtained as a white solid. LCMS: Rt = 0.336 min, m / z = 244.8 (MH + )

[0445] Compound 2 (343.10 mg, 1.40 mmol, 1 eq.), EDCI (402.57 mg, 2.10 mmol, 1.5 eq.) and DMAP (17.10 mg, 140.00 umol, 0.1 eq.) were added to a solution of compound 3 (430 mg, 1.40 mmol, 1 eq.) in DCM (8 mL) in a 40 mL glass bottle, and the mixture was stirred at 25 ° C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 0 / 1, desired product Rf=0.46) and the purified solution was concentrated under vacuum to give the product. Compound 4 (590 mg, 1.11 mmol, 78.99% yield) was obtained as a white solid. LCMS: Rt=0.419 min, m / z=535.0 (M+H + )

[0446] Compound 5 (428.36 mg, 1.69 mmol, 2 eq.), AcOK (165.55 mg, 1.69 mmol, 2 eq.) and Pd(dppf)Cl2.CH2Cl2 (68.88 mg, 84.34 umol, 0.1 eq.) were added to a solution of compound 4 (450 mg, 843.44 umol, 1 eq.) in dioxane (10 mL) in a 40 mL glass bottle and the mixture was stirred at 25 ° C for 12 h. The reaction mixture was quenched by adding H2O (30 mL) and extracted with dichloromethane (30 mL x3). The combined organic layers were washed with brine (100 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 0 / 1, desired product Rf=0.30). Compound 6 (190 mg, 289.99 umol, 62.39% yield) was obtained as a yellow oil. LCMS: Rt=0.439 min, m / z=581.2 (M+H + )

[0447] Compound 7 (48.58 mg, 258.35 umol, 1 eq.), K2CO3 (71.41 mg, 516.71 umol, 2 eq.) and Pd (dppf) Cl2 · CH2Cl2 (21.10 mg, 25.84 umol, 0.1 eq.) were added to a solution of compound 6 (150 mg, 258.35 umol, 1 eq.) in dioxane (5 mL) in a 40 mL glass bottle. The mixture was stirred at 100 ° C under N2 atmosphere for 12 hours. The reaction mixture was quenched by adding H2O (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layer was washed with brine (60 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. Then, the residue was purified by preparative-TLC (SiO2, PE: EtOAc = 0: 1) to obtain the product. Compound 8 (100 mg, 178.01 umol, 68.90% yield) was obtained as a yellow oil. LCMS: Rt=0.448 min, m / z=562.5 (M+H + )

[0448] CsF (270.40 mg, 1.78 mmol, 65.63 uL, 10 equiv) was added to a solution of compound 8 (100 mg, 178.01 umol, 1 equiv) in DMF (2 mL) in an 8 mL glass bottle. The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was quenched by adding H2O (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (50 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (FA, column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 14%-44%, 8 min), and the purified product was lyophilized. 153 (20.2 mg, 46.30 umol, 26.01% yield, 98.9% purity) was obtained as a yellow solid. LCMS: Rt=0.356 min, m / z=432.3 (M+H + )1H NMR: (400 MHz, CHLOROFORM-d) δ=12.15-12.00 (m, 1H), 8.27-8.17 (m, 2H), 7.94 (s, 1H), 7.71-7.64 (m, 2H), 7.12-7.05 (m, 2H), 4.90 (s, 2H), 4.22 (q, J=7.0 Hz, 2H), 3.01 (s, 3H), 2.90-2.84 (m, 3H), 1.57-1.53 ​​(m, 3H).

[0449] Compound 099 was prepared in a manner similar to Scheme 19 and obtained as a white solid (7.2 mg, 16.02 umol, 13.27% yield). 1 H NMR: (400 MHz, chloroform-d) δ = 7.99 (s, 1H), 7.37 (dd, J = 2.2, 8.2 Hz, 1H), 7.23 (s, 1H), 7.13-7.11 (m, 2H), 7.08-7.03 (m, 3H), 6.97 (d, J = 2.1 Hz, 1H), 6.89-6.86 (m, 1H), 4.92 (s, 2H), 3.75-3.72 (m, 1H), 3.05 (s, 3H), 0.80-0.77 (m, 2H), 0.72-0.69 (m, 2H). LCMS: Rt = 0.449 min, m / z = 449.8 (M+H + ).

[0450] Solution 20

[0451]

[0452] CsF (30.37 mg, 199.93 umol, 7.37 uL, 1.5 equiv) and compound 2 (28.43 mg, 199.93 umol, 1.5 equiv) were added to a solution of compound 1 in THF (1.5 mL) at 0 ° C. The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was poured into H2O (70 mL) and extracted with DCM (50 mLx3). The combined organic matter was washed with saturated NaCl aqueous solution (40 mLx3), dried over Na2SO4 and concentrated to give a residue. The residue was purified by preparative-TLC (SiO2, PE / EtOAc=1 / 1). Compound 3 (62 mg, 97.99 umol, 73.52% yield) was obtained as a colorless oil. LCMS: Rt=0.539 min, m / z=633.4 (M+H + ).

[0453] To a solution of compound 3 in TFA (1 mL) and DCM (1 mL) in a 50 mL round-bottom flask. The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated under vacuum to give a residue. The crude product was purified by preparative-RP (column: Waters xbridge150*25mm 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 8min). After preparative-HPLC purification, the eluate was concentrated to remove the organic solvent. The residual aqueous solution was lyophilized to give a white solid. Compound 171 (22 mg, 43.78umol, 36.94% yield, 100% purity) was obtained as a white solid. LCMS: Rt=0.413min, m / z=503.1 (M+H + ).1H NMR: (400MHz, chloroform-d) δppm 1.38 (t, J=6.94Hz, 3H) 3.10 (s, 3H) 4.08 (q, J=6.88Hz, 2H) 4.91-4.98 (m, 1H) 5.02-5.10 (m, 1H) 5.57 (br d,J=6.13Hz,1H)7.02-7.13(m,3H)7.27-7.29(m,1H)7.31(br d,J=7.50Hz,1H)7.35-7.40(m,2H)8.38(s,2H)12.43-12.74(m,1H).

[0454] Solution 21

[0455]

[0456] Pd(OAc)2(217.36mg, 968.16umol, 0.2 eq.), DPPF(536.73mg, 968.16umol, 0.2 eq.) and TEA(1.47g, 14.52mmol, 2.02mL, 3 eq.) were added to a 75mL hydrogenation bottle containing a solution of compound 1(1.5g, 4.84mmol, 1 eq.) in MeOH(10mL), and the mixture was stirred at 80°C under CO(50psi) for 48h. After the reaction was completed, it was cooled to room temperature, the mixture was filtered under N2 and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography (SiO2, PE:EtOAc=20:1 to 5:1, desired product Rf=0.5). Compound 2(1.6g, 4.80mmol, 99.12% yield) was obtained as a colorless oil. LCMS: Rt=0.463min, m / z=334.2(M+H + ) 1H NMR: (400 MHz, chloroform-d) δ = 9.06-9.03 (m, 1H), 8.20 (s, 1H), 7.42-7.33 (m, 1H), 5.84 (s, 2H), 5.73-5.68 (m, 1H), 5.57-5.49 (m, 1H), 3.99-3.96 (m, 3H), 3.55-3.49 (m, 2H), 1.26 (br t, J = 7.1 Hz, 2H), -0.05 (s, 9H)

[0457] DIBAL-H (1M, 6.30mL, 3 equivalents) was added to a three-necked round bottle containing a solution of compound 2 (700mg, 2.10mmol, 1 equivalent) in THF (5mL) at -78°C, and the mixture was stirred at -78°C under N2 for 1 hour. The mixture was poured into a saturated NH4Cl (80mL) solution and extracted with EtOAc (50mL X3), and the combined organic phases were washed with brine (50mL), dried over anhydrous Na2SO4, and concentrated to give a crude product. The crude product was purified by column chromatography (SiO2, PE / EtOAc=10 / 1 to 0 / 1, desired product Rf=0.6). Compound 3 (63mg, 206.26umol, 9.83% yield) was obtained as a yellow oil. LCMS: Rt=0.371min, m / z=306.0 (M+H + )

[0458] To a 100 mL three-necked flask containing a solution of compound 3 (95 mg, 311.02 umol, 1 eq.) in THF (5 mL) was added NaH (18.66 mg, 466.53 umol, 60% purity, 1.5 eq.) at 0 ° C., and the mixture was stirred for 1 h at 0 ° C. Then, MeI (88.29 mg, 622.04 umol, 38.72 uL, 2 eq.) was added, and the mixture was stirred for 1 h at 20 ° C. The reaction mixture was poured into a saturated NH4Cl solution (50 mL) at 0 ° C., and extracted with EtOAc (50 mL x 2), and the combined organic phases were washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated to give a crude product. The residue was purified by preparative-TLC (SiO2, PE: EtOAc = 0: 1). Compound 4 (69 mg, 215.98 umol, 69.44% yield, purity not available) was obtained as a yellow oil. LCMS: Rt = 0.367 min, m / z = 319.9 (M+Na + )

[0459] The solution of compound 4 (65 mg, 203.46 umol, 1 equivalent) in DCM (10 mL) and MeOH (10 mL) in a 100 mL three-necked flask was treated with ozone (9.77 mg, 203.46 umol, 1 equivalent) for 30 min (15 psi) at -78 ° C, and then the mixture was purged with nitrogen for 0.5 h, and PPh (106.73 mg, 406.92 umol, 2 equivalents) dissolved in DCM (10 mL) was added dropwise to the mixture. The mixture was warmed to 20 ° C and stirred at 20 ° C for 1 h. After the reaction was completed, the mixture was concentrated to give a crude product. The residue was purified by preparative-TLC (SiO2, PE: EtOAc = 0: 1). Compound 5 (49 mg, 152.44 umol, 74.92% yield) was obtained as a yellow oil.

[0460] To a 100 mL round-bottom flask containing a solution of compound 5 (49 mg, 152.44 umol, 1 eq.) in MeOH (4 mL), THF (2 M, 381.09 uL, 5 eq.) and AcOH (915.41 ug, 15.24 umol, 8.72e-1 uL, 0.1 eq.) containing MeNH2 was added, and the mixture was stirred at 20°C for 2 h. Then, NaBH4 (17.30 mg, 457.31 umol, 3 eq.) was added at 0°C, and the mixture was stirred at 20°C for 1 h. After the reaction was complete, the reaction mixture was poured into NH4Cl (10 mL) and the temperature was controlled between 10 and 20°C, then Na2CO3 (1 g) was added to the mixture, the solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The solution was then triturated in DCM and MeOH and collected by filtration, the filtrate was concentrated under reduced pressure to give a residue. LCMS: Rt = 0.722 min, m / z = 377.3 (M+H + )

[0461] To a 50 mL round-bottom flask containing a solution of compound 6 (30 mg, 89.15 umol, 1 eq.) and compound 7 (23.20 mg, 89.15 umol, 1 eq.) in DCM (2 mL), EDCI (25.64 mg, 133.73 umol, 1.5 eq.) and DMAP (1.09 mg, 8.92 umol, 0.1 eq.) were added, and the mixture was stirred at 20 ° C for 12 h. The solution was evaporated on a water bath under reduced pressure using a rotary evaporator. The residue was purified by preparative-TLC (SiO2, PE: EtOAc = 0: 1). Compound 8 (50 mg, 69.11 umol, 77.52% yield, 80% purity) was obtained as a colorless oil. LCMS: Rt = 0.474 min, m / z = 579.3 (M + H+ )

[0462] To a 100 mL round-bottom flask containing a solution of compound 8 (50 mg, 69.11 umol, 80% purity, 1 eq.) in DCM (1 mL), TFA (1.54 g, 13.51 mmol, 1 mL, 195.41 eq.) was added, and the mixture was stirred at 20 ° C for 2 h. The mixture was concentrated to give a crude product, which was dissolved in MeOH (5 mL), and 1 g of Na2CO3 was added to the mixture, the mixture was stirred at 20 ° C for 0.5 h, and then the mixture was filtered and the filtrate was concentrated to give a crude product. The crude product was purified by preparative-HPLC (FA, column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10 min), and the purified solution was lyophilized to give a white solid. Compound 077 (16.6 mg, 36.90 umol, 53.39% yield, 99.7% purity) was obtained as a white solid. LCMS: Rt=0.384 min, m / z=449.2 (M+H + ) 1 H NMR: (400 MHz, CHLOROFORM-d) δ = 12.42-12.26 (m, 1H), 9.10-9.03 (m, 1H), 8.24 (s, 1H), 7.40-7.28 (m, 4H), 7.10-7.01 (m, 3H), 5.22 (s, 2H), 4.91-4.87 (m, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.54-3.47 (m, 3H), 3.05 (s, 3H), 1.37 (t, J = 6.9 Hz, 3H).

[0463] Solution 22

[0464]

[0465] To a solution of compound 1 (50 mg, 142.66 umol, 1 eq.) in THF (1 mL) was added tetradeuterium aluminum lithium (19.69 mg, 427.98 umol, 26.75 uL, 3 eq.) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour. After the reaction was complete, Na2SO4·10H2O (20 mg) was added to the resulting mixture. Then, the mixture was filtered, and the filtrate was concentrated in vacuo to give compound 2 (46 mg, 141.76 umol, 99.37% yield) as a yellow oil, which was used in the next step. LCMS: Rt=0.646 min, m / z=325.2 (M+H + )

[0466] To a round-bottom flask (50 mL) containing a solution of compound 2 (46 mg, 141.76 umol, 1 eq.) and compound 3 (36.89 mg, 141.76 umol, 1 eq.) in DCM (3 mL), EDCI (40.76 mg, 212.64 umol, 1.5 eq.) and DMAP (1.73 mg, 14.18 umol, 0.1 eq.) were added. The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative-TLC (SiO2, DCM: MeOH = 10: 1). The purified solution was concentrated in vacuo to give compound 4 (20 mg, 35.29 umol, 24.89% yield) as a colorless oil. LCMS: Rt = 0.711 min, m / z = 567.2 (M + H + )D%=94.6%

[0467] TFA (770.00 mg, 6.75 mmol, 0.5 mL, 191.36 equiv) was added to a round-bottom flask (50 mL) containing a solution of compound 4 (20 mg, 35.29 umol, 1 equiv) in DCM (0.5 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated to give a crude product. The residue was basified with Et3N to a pH of about 8. The residue was purified by preparative-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (NH3H2O)-ACN]; B%: 27%-57%, 8min). The purified solution was lyophilized to give 086 (2.6 mg, 5.80 umol, 16.44% yield, 97.4% purity) as a white solid. LCMS: Rt=0.651 min, m / z=437.1 (M+H + )D%=94.6%1H NMR (400MHz, CHLOROFORM-d)δ=8.41(s,1H),8.32(s,1H),7.40-7.35(m,2H),7.33-7.29(m,2H),7.11-7.04(m,3H),4.98(s,2H),4.11-4.04(m,2H),3.08(s,3H),1.38(t,J=7.0Hz,3H).

[0468] Solution 23

[0469]

[0470] To a solution of compound 1 (437.56 mg, 1.43 mmol, 1 eq.) and compound 2 (500 mg, 1.43 mmol, 1 eq.) in DCM (15 mL) was added EDCI (410.21 mg, 2.14 mmol, 1.5 eq.) and DMAP (17.43 mg, 142.66 umol, 0.1 eq.). The mixture was stirred at 20 ° C for 12 hours. LCMS (5-95AB / 0.8 min) showed that 68% of the desired mass was detected. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / 1 to 2 / 1), and the purified solution was concentrated in vacuo to give compound 3 (1.1 g, 1.38 mmol, 96.51% yield, 80% purity) as a yellow oil. LCMS: Rt=0.640 min, m / z=639.3 (M+H) +

[0471] At 0 ° C, LiBH4(149.95mg, 6.88mmol, 5 equivalents) was added to a round-bottom flask (100mL) containing a solution of compound 3 (1.1g, 1.38mmol, 80% purity, 1 equivalent) in MeOH (15mL). The mixture was stirred at 20 ° C for 12 hours. LCMS (5-95AB / 0.8min) showed that 50% of the required mass and 33% of compound 3 were detected. The reaction mixture was poured into a saturated NH4Cl aqueous solution (30mL) and extracted with ethyl acetate (30mL x 3), the combined organic phase was dried and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 1 to ethyl acetate: methanol=10 / 1), and the purified solution was concentrated in vacuo to obtain compound 4 (330mg, 539.94umol, 39.22% yield) in a yellow oil. LCMS: Rt=0.495min, m / z=611.8(M+H) +

[0472] TFA (1.54 g, 13.51 mmol, 1 mL, 165.09 equiv) was added to a round-bottom flask (50 mL) containing a solution of compound 4 (50 mg, 81.81 umol, 1 equiv) in DCM (1 mL). The mixture was stirred at 20 ° C for 5 hours. LCMS (5-95AB / 0.8 min) showed that 86% of the desired mass was detected. The reaction mixture was concentrated at 20 ° C and under reduced pressure to give a residue. The residue was dissolved in DCM (5 mL) and basified with NaHCO3 (5 mg) to a pH of about 7, then filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative-HPLC (column: Phenomenex luna C18150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 22%-52%, 9min). The purified solution was lyophilized to obtain 047 (12.4 mg, 25.50 umol, 31.17% yield, 98.9% purity) as a white solid. LCMS: Rt = 0.400 min, m / z = 481.1 (M+H) + 1H NMR (400 MHz, CHLOROFORM-d) δ=8.34(d, J=14.8 Hz, 2H),7.38-7.31(m, 3H),7.23(s, 2H),6.89(dd, J=1.0,9.0 Hz, 1H),5.20(s, 2H),4.97(s, 2H),3.75(td, J=3.0,5.8 Hz, 1H),3.09(s, 3H),0.83-0.77(m, 2H),0.76-0.68(m, 2H).

[0473] Example 2: THP-1 cell-based NLRP3 activation assay

[0474] THP-1 cells are cultured in complete medium (CM) until they reach exponential growth and achieve >90% viability. CM is composed of RPMI-1640 (+Glutamax) / 10% fetal bovine serum / 55 μM β-mercaptoethanol / penicillin / streptomycin. The cells are centrifuged and resuspended in CM containing 20nM or 500nM PMA to reach 1,000,000 cells / mL. Then, 150,000 cells (150 μL) are added to each well of a 96-well TC plate and incubated for 24 hours or 3 hours in a standard cell culture incubator (37°C; 5% CO2). After this incubation, the plate is tilted and the culture medium is carefully removed. Then, 200 μL of CM containing 100 ng / mL LPS is added to the well and the cells are incubated for another 3 hours. The culture medium is removed again and replaced with the Opti-Mem culture medium containing the test compound of a predetermined dilution in duplicate wells. After 30 min of preincubation with the test compound, Opti-Mem medium with the corresponding concentration of compound containing 10 μM nigericin (final concentration) was added to the wells and incubated for another 1 hour. The positive control wells contained Opti-Mem containing 10 μM nigericin in the absence of the test compound, while the negative control wells contained Opti-Mem alone. The supernatant was then transferred to a fresh 96-well plate for storage and the levels of IL-1β (human; DuoSet; R&D) and TNFα (human; DuoSet; R&D) and relative pyroptosis were determined using the CytoTox 96 kit (not frozen prior to testing; Promega). After removing the supernatant, the cells were plated using The luminescent cell viability assay (Promega) was used to determine the relative viability of adherent cells in 96-well TC plates.

[0475] Table 6 below provides the IC values ​​of the compounds disclosed herein: 50 Data, where “+” indicates an IC < 50uM 50 Values, "++" indicates an IC < 10uM 50 value, and "+++" indicates an IC of <1uM 50 value.

[0476] Table 6

[0477]

[0478]

[0479]

[0480] The scope of the disclosed subject matter should not be limited by the specific embodiments and examples described herein. In fact, from the foregoing description and the accompanying drawings, various modifications of the present disclosure, in addition to those described, will become apparent to those skilled in the art. Such modifications are intended to fall within the scope of the appended claims.

[0481] All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated herein by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. A method of inhibiting NLRP3 inflammasome in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or 2 or the pharmaceutical composition of claim 3.

5. A method of treating inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or 2 or the pharmaceutical composition of claim 3.

6. A method for treating inflammatory senescence in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or 2 or the pharmaceutical composition of claim 3.

7. A method for treating a sensory neurological disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or 2 or the pharmaceutical composition of claim 3.

8. The method of claim 7, wherein the sensory neurological disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), traumatic brain injury, Parkinson's disease, and Alzheimer's disease.

9. The method of claim 7 or 8, wherein the sensory nerve disease is ALS.

10. The method of claim 7 or 8, wherein the sensory neurological disease is traumatic brain injury.

11. The method of claim 7 or 8, wherein the sensory neurological disease is Parkinson's disease.

12. The method of claim 7 or 8, wherein the sensory neurological disease is Alzheimer's disease.

13. A method of treating inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof; in R 1 is C optionally substituted with a substituent selected from the following 1-6 Alkyl: halogen, OH, OC 1-3 Alkyl, NH2, N(H)C 1-3 Alkyl, N(C 1-6 Alkyl)2, C(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; Each R 2 independently selected from halogen, C 1-3 Haloalkyl, OH, OC 1-3 Alkyl, OC 3-6 Cycloalkyl and C 3-6 Cycloalkyl; R 3 Selected from H, halogen, C 1-3 Haloalkyl, OH, OC 1-3 Alkyl, OC 3-6 Cycloalkyl, CN and C 3-6 cycloalkyl; and n is 0, 1 or 2.

14. The method of claim 13, wherein R 1 is C optionally substituted with OH 1-6 alkyl; Each R 2 independently selected from halo and C 3-6 Cycloalkyl; R 3 is a halogen group; and n is 1 or 2.

15. The method of claim 13 or 14, wherein the compound of formula I is selected from or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 13-15, wherein the compound of formula I is selected from or a pharmaceutically acceptable salt thereof.

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